Macrocylic oximyl hepatitis c protease inhibitors

ABSTRACT

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof:  
                 
which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/811,464, filed on Jun. 6, 2006, and U.S. Provisional Application No.60/______, which was converted from U.S. application Ser. No. 11/502,740filed Aug. 11, 2006. The entire teachings of the above applications areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel hepatitis C virus (HCV) proteaseinhibitor compounds having antiviral activity against HCV and useful inthe treatment of HCV infections. More particularly, the inventionrelates to HCV protease inhibitor compounds, compositions containingsuch compounds and methods for using the same, as well as processes formaking such compounds.

BACKGROUND OF THE INVENTION

HCV is the principal cause of non-A, non-B hepatitis and is anincreasingly severe public health problem both in the developed anddeveloping world. It is estimated that the virus infects over 200million people worldwide, surpassing the number of individuals infectedwith the human immunodeficiency virus (HIV) by nearly five fold. HCVinfected patients, due to the high percentage of individuals inflictedwith chronic infections, are at an elevated risk of developing cirrhosisof the liver, subsequent hepatocellular carcinoma and terminal liverdisease. HCV is the most prevalent cause of hepatocellular cancer andcause of patients requiring liver transplantations in the western world.

There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

Only two approved therapies for HCV infection are currently available.The original treatment regimen generally involves a 3-12 month course ofintravenous interferon-alpha (IFN-α), while a new approvedsecond-generation treatment involves co-treatment with IFN-α and thegeneral antiviral nucleoside mimics like ribavirin. Both of thesetreatments suffer from interferon-related side effects as well as lowefficacy against HCV infections. There exists a need for the developmentof effective antiviral agents for treatment of HCV infection due to thepoor tolerability and disappointing efficacy of existing therapies.

In a patient population where the majority of individuals arechronically infected and asymptomatic and the prognoses are unknown, aneffective drug preferably possesses significantly fewer side effectsthan the currently available treatments. The hepatitis C non-structuralprotein-3 (NS3) is a proteolytic enzyme required for processing of theviral polyprotein and consequently viral replication. Despite the hugenumber of viral variants associated with HCV infection, the active siteof the NS3 protease remains highly conserved thus making its inhibitionan attractive mode of intervention. Recent success in the treatment ofHIV with protease inhibitors supports the concept that the inhibition ofNS3 is a key target in the battle against HCV.

HCV is a flaviridae type RNA virus. The HCV genome is enveloped andcontains a single strand RNA molecule composed of circa 9600 base pairs.It encodes a polypeptide comprised of approximately 3010 amino acids.

The HCV polyprotein is processed by viral and host peptidase into 10discreet peptides which serve a variety of functions. There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are sixnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease.

The NS3-NS4A protease is responsible for cleaving four sites on theviral polyprotein. The NS3-NS4A cleavage is autocatalytic, occurring incis. The remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5Ball occur in trans. NS3 is a serine protease which is structurallyclassified as a chymotrypsin-like protease. While the NS serine proteasepossesses proteolytic activity by itself, the HCV protease enzyme is notan efficient enzyme in terms of catalyzing polyprotein cleavage. It hasbeen shown that a central hydrophobic region of the NS4A protein isrequired for this enhancement. The complex formation of the NS3 proteinwith NS4A seems necessary to the processing events, enhancing theproteolytic efficacy at all of the sites.

A general strategy for the development of antiviral agents is toinactivate virally encoded enzymes, including NS3, that are essentialfor the replication of the virus. Current efforts directed toward thediscovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause,Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status andEmerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002). Morerelevant patent disclosures describing the synthesis of HCV proteaseinhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543(2000); WO 99/50230 (1999); U.S. Pat. No. 5,861,297 (1999); USpublications 20050153877, 20050261200 and 20050065073.

SUMMARY OF THE INVENTION

The present invention relates to novel HCV protease inhibitor compoundsincluding pharmaceutically acceptable salts, esters, or prodrugs thereofwhich inhibit serine protease activity, particularly the activity ofhepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compoundsof the present invention interfere with the life cycle of the hepatitisC virus and are also useful as antiviral agents. The present inventionfurther relates to pharmaceutical compositions comprising theaforementioned compounds, salts, esters or prodrugs for administrationto a subject suffering from HCV infection. The present invention furtherfeatures pharmaceutical compositions comprising a compound of thepresent invention (or a pharmaceutically acceptable salt, ester orprodrug thereof) and another anti-HCV agent, such as alpha-interferon,beta-interferon, ribavirin, amantadine, another HCV protease inhibitor,or an HCV polymerase, helicase or internal ribosome entry siteinhibitor. The invention also relates to methods of treating an HCVinfection in a subject by administering a pharmaceutical composition ofthe present invention.

In one embodiment of the present invention, there are disclosedcompounds of formula I:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein:

-   R₁ and R₂ are independently selected from the group consisting of:    -   a) hydrogen;    -   b) aryl;    -   c) substituted aryl;    -   d) heteroaryl;    -   e) substituted heteroaryl;    -   f) heterocyclic or substituted heterocyclic;    -   g) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   h) substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N;    -   i) —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl;    -   j) —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl;    -   k) —B—R₃, where B is (CO), (CO)O, (CO)NR₄, (SO), (SO₂),        (SO₂)NR₄; and R₃ and R₄ are independently selected from the        group consisting of:        -   (i) Hydrogen;        -   (ii) aryl;        -   (iii) substituted aryl;        -   (iv) heteroaryl;        -   (v) substituted heteroaryl;        -   (vi) heterocyclic;        -   (vii) substituted heterocyclic;        -   (viii) —C₁-C₈ alkyl; —C₂-C₈ alkenyl, —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S or            N;        -   (xi) substituted —C₁-C₈ alkyl; substituted —C₂-C₈ alkenyl;            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N;        -   (x) —C₃-C₁₂ cycloalkyl; substituted —C₃-C₁₂ cycloalkyl;        -   (xvi) —C₃-C₁₂ cycloalkenyl, and substituted —C₃-C₁₂            cycloalkenyl;            alternatively, R₁ and R₂ taken together with the carbon atom            to which they are attached form cyclic moiety consisting of:            substituted or unsubstituted cycloalkyl, cycloalkenyl, or            heterocyclic; substituted or unsubstituted cycloalkyl,            cycloalkenyl, or heterocyclic each fused with one or more            R₃; where R₃ is as previously defined;-   G is -E-R₃where E is absent, or E is O, CO, (CO)O, (CO)NH, NH,    NH(CO), NH(CO)NH, NH(SO₂)NH or NHSO₂; where R₃ is as previously    defined;-   Z is selected from the group consisting of CH₂, O, S, SO, or SO₂;-   A is selected from the group consisting of R₅, (CO)R₅, (CO)OR₅,    (CO)NHR₅, SO₂R₅, (SO₂)OR₅ and SO₂NHR₅;-   R₅ is selected from the group consisting of:    -   1) aryl;    -   2) substituted aryl;    -   3) heteroaryl;    -   4) substituted heteroaryl;    -   5) heterocyclic;    -   6) substituted heterocyclic;    -   7) —C₁-C₈ alkyl; —C₂-C₈ alkenyl; —C₂-C₈ alkynyl each containing        0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   8) substituted —C₁-C₈ alkyl; substituted —C₂-C₈ alkenyl;        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N;    -   9) —C₃-C₁₂ cycloalkyl;    -   10) substituted —C₃-C₁₂ cycloalkyl;    -   11) —C₃-C₁₂ cycloalkenyl,; and    -   12) substituted —C₃-C₁₂ cycloalkenyl;    -   j=0, 1, 2,or 3;    -   k=0, 1, 2, or 3; and    -   m=0, 1, 2 or 3;    -   n=1, 2 or 3; and    -   h=0, 1, 2, or 3.

In another embodiment, the present invention features pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt, ester or prodrug thereof. In stillanother embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier or excipient. In yet another embodiment of theinvention are methods of treating a hepatitis C infection in a subjectin need of such treatment with said pharmaceutical compositions.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention is a compound of formula Ias illustrated above, or a pharmaceutically acceptable salt, ester orprodrug thereof.

In another embodiment, the present invention relates to a compound offormula II, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where A, G and R₁ are as previously defined. In a preferred example, R₁is not hydrogen.

In another example, R₁ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂ cycloalkenyl. Ais selected from the group consisting of R₅, —C(O)—R₅, —C(O)—O—R₅ and—C(O)—NH—R₅, where R₅ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂—R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In still another example, R₁ is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—O—R₅ or—C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl,substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈alkynyl, —C₃-C₁₂ cycloalkyl, -C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G is —NHSO₂—R₃, whereR₃ is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted—C₃-C₁₂ cycloalkenyl.

In still yet another example, R₁ is selected from the group consistingof aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—O—R₅, where R₅ is—C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₁ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic. A is —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl. G is —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl.

In yet another example, R₁ is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—R₅, where R₅ issubstituted —C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and issubstituted with (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₁ is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—R₅, where R₅ issubstituted methyl and is substituted at least with (1) aryl orheteroaryl and (2) —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or —NHC(O)-heteroaryl. G is—NHSO₂—R₃, where R₃ is —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl.

In another example, R₁ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic. A is —R₅, where R₅ is —C₁-C₈ alkyl orsubstituted —C₁-C₈ alkyl. G is —NHSO₂—R₃, where R₃ is selected fromaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In one embodiment, the present invention relates to a compound offormula III, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where A, G, R₁ and R₂ are as previously defined in the first embodiment.In a preferred example, R₁ and R₂ are not both hydrogen.

In another example, R₁ and R₂ are independently selected from the groupconsisting of aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted—C₃-C₁₂ cycloalkenyl; or R₁ and R₂ taken together with the carbon atomto which they are attached form a cyclic moiety selected from from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A canbe selected from the group consisting of —R₅, —C(O)—R₅, —C(O)—O—R₅ and—C(O)—NH—R₅, where R₅ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂—R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In a preferred example, R₁ and R₂ taken together with the carbon atom towhich they are attached form a cyclic moiety selected from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl,—C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl,substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form a cyclic moiety selected from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—O—R₅, where R₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃is selected from —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In still another preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl. A is —C(O)—O—R₅,where R₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In yet another preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form a cyclic moiety selectedfrom (1) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic, or (2) substituted or unsubstituted cycloalkyl,cycloalkenyl or heterocyclic each fused with one or more R₃, where eachR₃ is independently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃is selected from —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.Preferably, R₁ and R₂ taken together with the carbon atom to which theyare attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form a cyclic moiety selected from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—R₅, where R₅ is substituted —C₁-C₈ alkyl (e.g., substituted methylor ethyl) and is substituted with (1) aryl or heteroaryl, (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl, and optionally (3) one or more othersubstituents. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In yet another preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl. A is —C(O)—R₅,where R₅ is substituted methyl and is substituted at least with (1) arylor heteroaryl and (2) —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or —NHC(O)-heteroaryl. G is—NHSO₂—R₃, where R₃ is —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl. A is —R₅, whereR₅ is —C₁-C₈ alkyl or substituted —C₁-C₈ alkyl. G is —NHSO₂—R₃, where R₃is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted—C₃-C₁₂ cycloalkenyl.

In further embodiment, the present invention relates to a compound offormula IV, or a pharmaceutically acceptable salt, ester or prodrugthereof:

wherein V is absent, or V is CO, O, S, SO, SO₂, NH or NCH₃, or(CH₂)_(q); where q is 1, 2, 3 or 4; and where X and Y are independentlyselected from the group consisting of: (i) aryl; substituted aryl; (ii)heteroaryl; substituted heteroaryl; (iii) heterocyclic; substitutedheterocyclic; where A and G are as previously defined in the firstembodiment.

In one example,

is selected from

wherein X₁-X₈ are independently selected from CH and N and X₁-X₈ can befurther substituted when it is a CH, and Y₁-Y₃ are independentlyselected from CH, N, NH, S and O and Y₁-Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A can be selected from the group consisting of R₅, —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH−R₃ or —NHSO₂—R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In still another example,

is selected from

and wherein X₁-X₈ are independently selected from CH and N and X₁-X₈ canbe further substituted when it is a CH, and Y₁-Y₃ are independentlyselected from CH, N, NH, S and O and Y₁-Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still yet another example,

is selected from

wherein X₁-X₈ are independently selected from CH and N and X₁-X₈ can befurther substituted when it is a CH, and Y₁-Y₃ are independentlyselected from CH, N, NH, S and O and Y₁-Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example,

is selected from

wherein X₁-X₈ are independently selected from CH and N and X₁-X₈ can befurther substituted when it is a CH, and Y₁-Y₃ are independentlyselected from CH, N, NH, S and O and Y₁-Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A is —C(O)—R₅, where R₅ is substituted —C₁-C₈ alkyl (e.g.,substituted methyl or ethyl) and is substiututed with (1) aryl orheteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂-C₂-C₁₂-alkenyl, —NHC(O)-aryl or —NHC(O)-heteroaryl, andoptionally (3) one or more other substituents. G is —NHSO₂—R₃, where R₃is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted—C₃-C₁₂ cycloalkenyl.

In a preferred example, R₁ and R₂ taken together with the carbon atom towhich they are attached form

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or 3. A is —C(O)—O—R₅ or —C(O)—NH—R₅, whereR₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, orsubstituted —C₃-C₁₂ cycloalkenyl. G is —NHSO₂—R₃, where R₃ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In a preferred example, R₁ and R₂ taken together with the carbon atom towhich they are attached form

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or 3. A is —C(O)—R₅, where R₅ is substituted—C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and is substiututedwith (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In a most preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl,—C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl,substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. Gis —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl.

In a most preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl,—C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl,substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. Gis —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl.

In anoter preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or 3. A is —R₅, where R₅ is —C₁-C₈ alkyl orsubstituted —C₁-C₈ alkyl. G is —NHSO₂—R₃, where R₃ is selected fromaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In one embodiment, the present invention relates to a compound offormula V, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where X₁-X₄ are independently selected from CO, CH, NH, O and N; andwherein X₁-X₄ can be further substituted when any one of X₁-X₄ is CH orNH; where R₆ and R₇ are independently R₃; where R₃ is independentlyselected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) aryl;    -   (iii) substituted aryl;    -   (iv) heteroaryl;    -   (v) substituted heteroaryl;    -   (vi) heterocyclic;    -   (vii) substituted heterocyclic;    -   (viii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   (ix) substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N;    -   (x) —C₃-C₁₂ cycloalkyl, or —C₃-C₁₂ cycloalkenyl;    -   (xi) substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂        cycloalkenyl; and where A, G and V are as previously defined in        the embodiment immediately above. Alternatively, R₆ and R₇ can        be independently selected from halogen, oxo, thioxo, nitro,        cyano, —OR₃, —SR₃, —NR₃R₄, —SOR₃, —SO₂R₃, —NHSO₂R₃, —SO₂NHR        —COR₃, —CO₂R₃, (CO)NHR₃, —OCOR₃, OCONHR₃, NHCO₂R₃, —NH(CO)R₃,        —NH(CO)NHR₃, and —NH(SO₂)NHR₃.

In one example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is selected from the group consisting of R₅, —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃′,—NH—C(O)—R₃′, —NH—SO₂—NH—R₃′ or —NHSO₂—R₃′, where R₃′ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃′, where R₃′ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—O—R₅, where R₅ is —C₁-C₈alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted—C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃′, where R₃′ is selected from —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, substituted—C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is—NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkyl or substituted—C₃-C₁₂ cycloalkyl.

In yet another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substituted—C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and is substiututedwith (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substitutedmethyl and is substiututed at least with (1) aryl or heteroaryl and (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl. G is —NHSO₂—R₃, where R₃ is —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —R₅, where R₅ is —C₁-C₈ alkyl or substituted —C₁-C₈alkyl. G is —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In one embodiment, the present invention relates to a compound offormula VI, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where Y₁-Y₃ are independently selected from CO, CH, NH, N, S and O; andwhere Y₁-Y₃ can be further substituted when any one of Y₁-Y₃ is CH orNH; Y₄ is selected from C, CH and N; and where A, G, R_(6,) R₇ and V areas previously defined.

In one example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is selected from the group consisting of —R₅, —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃′,—NH—C(O)—R₃′, —NH—SO₂—NH—R₃′ or —NHSO₂—R₃′, where R₃′ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃′, where R₃′ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—O—R₅, where R₅ is —C₁-C₈alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted—C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃′, where R₃′ is selected from —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, substituted—C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is—NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkyl or substituted—C₃-C₁₂ cycloalkyl.

In yet another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substituted—C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and is substiututedwith (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substitutedmethyl and is substiututed at least with (1) aryl or heteroaryl and (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂-C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl. G is —NHSO₂—R₃, where R₃ is —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —R₅, where R₅ is —C₁-C₈ alkyl or substituted —C₁-C₈alkyl. G is —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In another embodiment, the present invention relates to a compound offormula VII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where A, G and R₁ are as previously defined. In a preferred example, R₁is not hydrogen.

In another example, R₁ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂ cycloalkenyl. Ais selected from the group consisting of —R₅, —C(O)—R₅, —C(O)—O—R₅ and—C(O)—NH—R₅, where R₅ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂—R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In still another example, R₁ is selected from the group consisting ofaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—O—R₅ or—C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl,substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G is —NHSO₂—R₃, whereR₃ is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted—C₃-C₁₂ cycloalkenyl.

In still yet another example, R₁ is selected from the group consistingof aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—O—R₅, where R₅ is—C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₁ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic. A is —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl. G is —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl.

In still yet another example, R₁ is selected from the group consistingof aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic. A is —C(O)—R₅, where R₅ issubstituted —C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and issubstiututed with (1) aryl or heteroaryl, (2)) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In another example, R₁ is selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic. A is —R₅, where R₅ is —C₁-C₈ alkyl orsubstituted —C₁-C₈ alkyl. G is —NHSO₂—R₃, where R₃ is selected fromaryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In another embodiment, the present invention relates to a compound offormula VIII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where A, G, R₁ and R₂ are as previously defined in the first embodiment.In a preferred example, R₁ and R₂ are not both hydrogen.

In another example, R₁ and R₂ are independently selected from the groupconsisting of aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted—C₃-C₁₂ cycloalkenyl; or R₁ and R₂ taken together with the carbon atomto which they are attached form a cyclic moiety selected from from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A canbe selected from the group consisting of —R₅, —C(O)—R₅, —C(O)—O—R₅ and—C(O)—NH—R₅, where R₅ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂—R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In a preferred example, R₁ and R₂ taken together with the carbon atom towhich they are attached form a cyclic moiety selected from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, —C₂-C₈ alkenyl,—C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl,substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form a cyclic moiety selected from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—O—R₅, where R₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃is selected from —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In still another preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl. A is —C(O)—R₅,where R₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In yet another preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form a cyclic moiety selectedfrom (1) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic, or (2) substituted or unsubstituted cycloalkyl,cycloalkenyl or heterocyclic each fused with one or more R₃, where eachR₃ is independently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃is selected from —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.Preferably, R₁ and R₂ taken together with the carbon atom to which theyare attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form a cyclic moiety selected from (1)substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclic,or (2) substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclic each fused with one or more R₃, where each R₃ isindependently selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic or substituted heterocyclic. A is—C(O)—R₅, where R₅ is substituted —C₁-C₈ alkyl (e.g., substituted methylor ethyl) and is substiututed with (1) aryl or heteroaryl, (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl, and optionally (3) one or more othersubstituents. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In yet another preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl. A is —C(O)—R₅,where R₅ is substituted methyl and is substiututed at least with (1)aryl or heteroaryl and (2) —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or —NHC(O)-heteroaryl. G is—NHSO₂—R₃, where R₃ is —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

which is optionally substituted with one or more groups, and each groupis independently selected from halogen, hydroxy, nitro, cyano, amino,formyl, —C₁-C₈alkyl or —C₂-C₈alkenyl, or —C₂-C₈alkynyl. A is —R₅, whereR₅ is —C₁-C₈ alkyl or substituted —C₁-C₈ alkyl. G is —NHSO₂—R₃, where R₃is selected from aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl,—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted—C₃-C₁₂ cycloalkenyl.

In one embodiment, the present invention relates to a compound offormula IX, or a pharmaceutically acceptable salt, ester or prodrugthereof:

wherein V is absent, or V is CO, O, S, SO, SO₂, NH or NCH₃, or(CH₂)_(q); where q is 1, 2, 3 or 4; and where X and Y are independentlyselected from the group consisting of: (i) aryl; substituted aryl; (ii)heteroaryl; substituted heteroaryl; (iii) heterocyclic; substitutedheterocyclic; where A and G are as previously defined in the firstembodiment.

In one example,

is selected from

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A can be selected from the group consisting of —R₅, —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂—R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In still another example,

is selected from

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still yet another example,

is selected from

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S. NH, or (CH₂)_(q), where q is1, 2 or 3. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl. G is —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl.

In another example,

is selected from

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or 3. A is —C(O)—R₅, where R₅ is substituted —C₁-C₈ alkyl (e.g.,substituted methyl or ethyl) and is substiututed with (1) aryl orheteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-arylor —NHC(O)-heteroaryl, and optionally (3) one or more othersubstituents. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In a preferred example, R₁ and R₂ taken together with the carbon atom towhich they are attached form

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or 3. A is —C(O)—O—R₅ or —C(O)—NH—R₅, whereR₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In a preferred example, R₁ and R₂ taken together with the carbon atom towhich they are attached form

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or 3. A is —C(O)—R₅, where R₅ is substituted—C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and is substiututedwith (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In a most preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl, substituted—C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is—NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkyl or substituted—C₃-C₁₂ cycloalkyl.

In another most preferred example, R₁ and R₂ taken together with thecarbon atom to which they are attached form

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —C(O)—R₅, where R₅ is substituted —C₁-C₈ alkyl (e.g., substitutedmethyl or ethyl) and is substiututed with (1) aryl or heteroaryl, (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl, and optionally (3) one or more othersubstituents. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In another preferred example, R₁ and R₂ taken together with the carbonatom to which they are attached form

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —R₅, where R₅ is —C₁-C₈ alkyl or substituted —C₁-C₈ alkyl. G is—NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, orsubstituted —C₃-C₁₂ cycloalkenyl.

In one embodiment, the present invention relates to a compound offormula X, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where X₁—X₄ are independently selected from CO, CH, NH, O and N; andwherein X₁—X₄ can be further substituted when any one of X₁—X₄ is CH orNH; where R₆ and R₇ are independently R₃; where R₃ is independentlyselected from the group consisting of:

-   -   (i) hydrogen;    -   (ii) aryl;    -   (iii) substituted aryl;    -   (iv) heteroaryl;    -   (v) substituted heteroaryl;    -   (vi) heterocyclic;    -   (vii) substituted heterocyclic;    -   (viii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   (ix) substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N;    -   (x) —C₃-C₁₂ cycloalkyl, or —C₃-C₁₂ cycloalkenyl;    -   (xi) substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂        cycloalkenyl;        and where A, G and V are as previously defined in the embodiment        immediately above. Alternatively, R₆ and R₇ can be independently        selected from halogen, oxo, thioxo, nitro, cyano, —OR₃, —SR₃,        —NR₃R₄, —SOR₃, —SO₂R₃, —NHSO₂R₃, —SO₂NHR₃, —COR₃, —CO₂R₃,        (CO)NHR₃, —OCOR₃, OCONHR₃, NHCO₂R₃, —NH(CO)R₃, —NH(CO)NHR₃, and        —NH(SO₂)NHR₃.

In one example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is selected from the group consisting of —R₅, —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃′,—NH—C(O)—R₃′, —NH—SO₂—NH—R₃′ or —NHSO₂—R₃′, where R₃′ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C- alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃′, where R₃′ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—O—R₅ or —C(O)—NH—R₅, whereR₅ is —C₁-C₈ alkyl, substituted —C₁-C₈ alkyl, —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃′, where R₃′ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In yet another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substituted—C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and is substiututedwith (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substitutedmethyl and is substiututed at least with (1) aryl or heteroaryl and (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl. G is —NHSO₂—R₃, where R₃ is —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —R₅, where R₅ is —C₁-C₈ alkyl or substituted —C₁-C₈alkyl. G is —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In one embodiment, the present invention relates to a compound offormula XI, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where Y₁—Y₃ are independently selected from CO, CH, NH, N, S and O; andwhere Y₁—Y₃ can be further substituted when any one of Y₁—Y₃ is CH orNH; Y₄ is selected from C, CH and N; and where A, G, R₆, R₇ and V are aspreviously defined.

In one example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is selected from the group consisting of —R₅, —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃′,—NH—C(O)—R₃′, —NH—SO₂—NH—R₃′ or —NHSO₂—R₃′, where R₃′ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —C(O)—O—R₅ or —C(O)—NH—R₅, where R₅ is —C₁-C₈ alkyl,—C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted—C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃′, where R₃′ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—O—R₅ or —C(O)—NH—R₅, whereR₅ is —C₁-C₈ alkyl, substituted —C_(1-C) ₈ alkyl, —C₃-C₁₂ cycloalkyl orsubstituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃′, where R₃′ is selectedfrom —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In yet another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substituted—C₁-C₈ alkyl (e.g., substituted methyl or ethyl) and is substiututedwith (1) aryl or heteroaryl, (2) —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂-C₂-C₁₂-alkenyl, —NHC(O)-aryl or—NHC(O)-heteroaryl, and optionally (3) one or more other substituents. Gis —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In still another example, R₆ and R₇ are independently selected from thegroup consisting of hydrogen, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, andsubstituted —C₃-C₁₂ cycloalkenyl. A is —C(O)—R₅, where R₅ is substitutedmethyl and is substiututed at least with (1) aryl or heteroaryl and (2)—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHC(O)-aryl or —NHC(O)-heteroaryl. G is —NHSO₂—R₃, where R₃ is —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.

In another example, R₆ and R₇ are independently selected from the groupconsisting of hydrogen, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, —C₁-C₈ alkyl, —C₂-C₈alkenyl, —C₂-C₈ alkynyl, substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, substituted —C₂-C₈ alkynyl, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, and substituted —C₃-C₁₂cycloalkenyl. A is —R₅, where R₅ is —C₁-C₈ alkyl or substituted —C₁-C₈alkyl. G is —NHSO₂—R₃, where R₃ is selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl.

In one embodiment of the present invention, there are disclosedcompounds of formula XII:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein:

-   M₁ is selected from the group consisting of:

(1) —N═CR₃₁R₃₂;

wherein R₃, and R₃₂ are independently selected from the group consistingof:

-   -   a) hydrogen;    -   b) aryl; substituted aryl;    -   c) heteroaryl; substituted heteroaryl;    -   d) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl containing 0,        1, 2, or 3 heteroatoms selected from O, S or N; optionally        substituted with one or more substituents selected from halogen,        aryl, substituted aryl, heteroaryl, or substituted heteroaryl;    -   e) —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl;        —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl;        heterocyclic or substituted heterocyclic;    -   f) -A-R₃₀, where A is (CO), (CO)O, (CO)NR₄₀, (SO), (SO₂),        (SO₂)NR₄₀; and R₃₀ and R₄₀ are independently selected from the        group consisting of:        -   (i) Hydrogen;        -   (ii) aryl; substituted aryl; heteroaryl; substituted            heteroaryl        -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl            containing 0, 1, 2, or 3 heteroatoms selected from O, S or            N, optionally substituted with one or more substituents            selected from halogen, aryl, substituted aryl, heteroaryl,            or substituted heteroaryl; —C₃-C₁₂ cycloalkyl, or            substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or            substituted —C₃-C₁₂ cycloalkenyl; heterocyclic or            substituted heterocyclic;    -   with added proviso that when A=CO, (CO)O, (SO), (SO₂), R₃₀ is        not hydrogen; with added proviso that when R₃₁=hydrogen, R₃₂ is        not hydrogen;        alternatively, R₃₁ and R₃₂ are taken together with the carbon        atom to which they are attached to form the group consisting of:    -   a) —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl;        —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl        heterocyclic or substituted heterocyclic;    -   b) —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl, —C₃-C₁₂        cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; heterocyclic        or substituted heterocyclic fused with one or more substituents        selected from aryl, substituted aryl, heteroaryl, substituted        heteroaryl, —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl,        —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl;        heterocyclic or substituted heterocyclic;    -   c) x ; wherein V is absent, or V is O, S, SO, SO₂, NR₅₀, or        (CH₂)_(q); where R₅₀ is selected from H, OH, OCH₃, —O—C₁-C₈        alkyl, —C₁-C₈ alkyl, —O—C₃-C₈ cycloalkyl, —C₃-C₈ cycloalkyl,        —O—C₃-C₈ cycloalkenyl; —C₃-C₈ cycloalkenyl; where q is 1, 2, 3        or 4; and    -   where X and Y are independently selected from the group        consisting of:        -   (i) aryl; substituted aryl;        -   (ii) heteroaryl; substituted heteroaryl;        -   (iii) heterocyclic; substituted heterocyclic;    -   (2) NR₃₀R₄₀; NR₅(CO)R₃₀; NR₅₀(CO)OR₃₀; NR₅₀(CO)NR₃₀R₄₀;        NR₅₀(SO₂)OR₃₀; NR₅₀(SO₂)NR₃₀R₄₀; where R₃₀, R₄₀ and R₅₀ are as        previously defined; alternatively, for formula (I), R₃₀ and R₄₀        are taken together with the nitrogen atom to which they are        attached to form the group consisting of: heterocyclic, or        substituted heterocyclic; heteroaryl, or substituted heteroaryl;

-   M₂ is selected from the group consisting of:    -   (1) oxygen;    -   (2) sulfur;    -   (3) NR₆₀; where R₆₀ is selected from H, OH, OCH₃, —O—C₁-C₈        alkyl, —C₁-C₈ alkyl;

-   G is -E-R₃₀; and where E is absent, or E is O, CO, (CO)O, (CO)NH,    NH, NH(CO), NH(CO)NH, NH(CNR₅₀)NH, NH(SO₂)NH or NHSO₂; where R₃₀ and    R₅₀ are as previously defined;

-   Z is selected from the group consisting of CH₂, O, CO, (CO)O,    (CO)NH, S, SO, SO₂, CF, CF₂, aryl, substituted aryl, heteroaryl and    substituted heteroaryl;

-   n=0, 1, 2, 3 or 4;

-   U is CH, CF or N;

-   R₇₀ is selected from the group consisting of H, OH, OCH₃, —O—C₁-C₈    alkyl, —C₁-C₈ alkyl;

-   J is selected from the group consisting of CO, (CO)O, (CO)NR₅₀, SO₂,    (SO₂)O or SO₂NR₅₀;

-   R₈₀ is selected from the group consisting of:    -   (1) hydrogen;    -   (2) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (3) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl containing        0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally        substituted with one or more substituents selected from halogen,        aryl, substituted aryl, heteroaryl, or substituted heteroaryl;        —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; heterocyclic        or substituted heterocyclic;        with added proviso that when J=CO, (CO)O, (SO), (S0₂), R₈₀ is        not hydrogen;

-   m=0, 1, 2 or 3; and

-   s=0, 1, 2 or 3.

In another embodiment of the present invention relates to compound offormula XIII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where G, J, M₂, R₃₁, R₇₀, and R₈₀ are as previously defined in theembodiment immediately above, with added proviso R₃₁ is not hydrogen.

Yet another embodiment of the present invention relates to compound offormula XIV, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where G, J, M₂, R₃₁, R₃₂, R₇₀, and R₈₀ are as previously defined in theembodiment above.

In another embodiment of the present invention relates to compound offormula XV, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where X₁ and Y₁ are independently selected from CH and N; R₉₀, R₁₀₀,R₁₁₀, and R₁₂₀ are independently R₃₀; G, J, M₂, R₇₀, and R₈₀ are aspreviously defined in the embodiment above.

In one embodiment of the present invention relates to compound offormulae XVI, or a pharmaceutically acceptable salt, ester or prodrugthereof:

where G, J, M₂, R₇₀, R₈₀, V, X and Y are as previously defined in theembodiment above.

In another embodiment of the present invention relates to compound offormula XVII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where X₁-X₄ are independently selected from CH and N; X₁-X₄ can befurther substituted when it is a CH; where G, J, M₂, R₇₀, R₈₀, R₉₀, R₁₀₀and V are as previously defined in the embodiment above.

In another embodiment of the present invention relates to compound offormula XVIII, or a pharmaceutically acceptable salt, ester or prodrugthereof:

Where Y₁—Y₃ are independently selected from CH, N, NH, S and O; andY₁—Y₃ can be further substituted when it is CH or NH; Y₄ is selectedfrom CH and N; where G, J, M₂, R₇₀, R₈₀, R₉₀, R₁₀₀ and V are aspreviously defined.

In one embodiment of the present invention relates to compound offormula XIX or a pharmaceutically acceptable salt, ester or prodrugthereof:

where W₁ is hydrogen, R₃₀, COR₃₀, CONR₃₀R₄₀, SOR₃₀, SO₂NR₃₀R₄₀; G, J,M₂, R₇₀ and R₈₀ are as previously defined.

In one embodiment of the present invention relates to compound offormula XX, or a pharmaceutically acceptable salt, ester or prodrugthereof:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein:

-   R₁₀₁ and R₁₀₂ are independently selected from the group consisting    of:    -   a) hydrogen;    -   b) aryl;    -   c) substituted aryl;    -   d) heteroaryl fused with 0, 1, 2, or 3 more group selected from        heteroaryl and aryl;    -   e) substituted heteroaryl fused with 0, 1, 2 or 3 more group        selected from heteroaryl, substituted heteroaryl, aryl and        substituted aryl;    -   f) heterocyclic, substituted heterocyclic, or oxo substituted        heterocyclic; wherein oxo refer to substituted by independent        replacement of two of the hydrogen atoms thereon with ═O;    -   g) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   h) substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N;    -   i) —C₃-C₁₂ cycloalkyl, or —C₃-C₁₂ cycloalkenyl;    -   j) substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂        cycloalkenyl;    -   k) oxo substituted —C₃-C₁₂ cycloalkyl, or oxo substituted        —C₃-C₁₂ cycloalkenyl;    -   l) —B—R₁₀₃, where B is (CO), (CO)O, (CO)NR₁₀₄, (SO), (SO₂),        (SO₂)NR₁₀₄; and R₁₀₃ and R₁₀₄ are independently selected from        the group consisting of:        -   (i) hydrogen;        -   (ii) aryl;        -   (iii) substituted aryl;        -   (iv) heteroaryl fused with 0, 1,2, or 3 more group selected            from aryl and heteroaryl;        -   (v) substituted heteroaryl fused with 0, 1,2 or 3 more group            selected from heteroaryl, substituted heteroaryl, aryl and            substituted aryl;        -   (vi) heterocyclic;        -   (vii) substituted heterocyclic;        -   (viii) oxo substituted heterocyclic;        -   (ix) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each            containing 0, 1, 2, or 3 heteroatoms selected from O, S or            N;        -   (x) substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or            substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3            heteroatoms selected from O, S or N;        -   (xi) —C₃-C₁₂ cycloalkyl, or —C₃-C₁₂ cycloalkenyl;        -   (xii) substituted —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂            cycloalkenyl, oxo substituted —C₃-C₁₂ cycloalkyl, or oxo            substituted —C₃-C₁₂ cycloalkenyl;            or R₁₀₁ and R₁₀₂ taken together with the carbon atom to            which they are attached form a cyclic moiety selected from:            substituted or unsubstituted cycloalkyl, cycloalkenyl, or            heterocyclic; substituted or unsubstituted cycloalkyl,            cycloalkenyl, or heterocyclic each substituted with an oxo;            substituted or unsubstituted cycloalkyl, cycloalkenyl, or            heterocyclic each fused with one or more R₁₀₃; or oxo            substituted or unsubstituted cycloalkyl, cycloalkenyl, or            heterocyclic each fused with one or more R₁₀₃;-   G₁ is -E-R₁₀₃, where E is absent or E is O, CO, (CO)O, (CO)NH, NH,    NH(CO), NH(CO)NH, NH(SO₂)NH or NHSO₂;-   Z is selected from the group consisting of CH₂, O, S, SO, or SO₂;-   A is selected from the group consisting of R₁₀₅, (CO)R₁₀₅,    (CO)OR₁₀₅, (CO)NHR₁₀₅, SO₂R105₅, (SO₂)OR₁₀₅ and SO₂NHR₁₀₅;-   R₁₀₅ is selected from the group consisting of: aryl;    -   a) hydrogen    -   b) substituted aryl;    -   c) heteroaryl fused with 0, 1, 2, or 3 more group selected from        heteroaryl and aryl;    -   d) substituted heteroaryl fused with 0, 1, 2 or 3 more group        selected from heteroaryl, substituted heteroaryl, aryl and        substituted aryl;    -   e) heterocyclic;    -   f) substituted heterocyclic;    -   g) oxo substituted heterocyclic;    -   h) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;    -   i) substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N;    -   j) —C₃-C₁₂ cycloalkyl, or —C₃-C₁₂ cycloalkenyl;    -   k) substituted —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂        cycloalkenyl, oxo substituted —C₃-C₁₂ cycloalkyl, or oxo        substituted —C₃-C₁₂ cycloalkenyl;-   j=0, 1, 2, or 3;-   k=0, 1, 2, or 3;and-   m=0, 1, 2 or 3;-   n=1, 2 or 3 and-   h=0, 1, 2, or 3.

Representative compounds according to the invention are those selectedfrom the group consisting of:Compounds (1)-(2) of the Formula A:

Rx and G are Delineated for Each Example in TABLE 1: TABLE 1 Compound RxG (1)

OEt (2)

OEtCompounds (3)-(113) of the Formula B:

R₁, R₂, Rx and G are Delineated for each Example in TABLE 2: TABLE 2Compound Rx R₁ R₂ G (3)

—CH₃ —Ph —OH (4)

—CH₂CH₃ —Ph —OH (5)

—CH₂CH₂CH₃ —Ph —OH (6)

—CH₂OCH₃ —Ph —OH (7)

—Ph —Ph —OH (8)

—Ph

—OH (9)

—Ph —OH (10)

—Ph —OH (11)

—Ph —OH (12)

—Ph —OH (13)

—H —Ph —OH (14)

—H

—OH (15)

—H

—OH (16)

—H

—OH (17)

—H

—OH (18)

—H

—OH (19)

—CH₂CH₃

—OH (20)

—H

—OH (21)

—H

—OH (22)

—H

—OH (23)

—H

—OH (24)

—H

—OH (25)

—H

—OH (26)

—H

—OH (27)

—H

—OH (28)

—H

—OH (29)

—H

—OH (30)

—H

—OH (31)

—H

—OH (32)

—H

—OH (33)

—H

—OH (34)

—H

—OH (35)

—H

—OH (36)

—H

—OH (37)

—H

—OH (38)

—H

(39)

—H

(40)

—H

(41)

—H

—OH (42)

—H

(43)

—Ph —Ph —OH (44)

—CH₃ —Ph —OH (45)

—H —Ph —OH (46)

—CH₃ —Ph

(47)

—CH₂CH₃ —Ph

(48)

—CH₂CH₂CH₃ —Ph

(49)

—CH₂OCH₃ —Ph

(50)

—Ph —Ph

(51)

—Ph

(52)

—Ph

(53)

—Ph

(54)

—Ph

(55)

—Ph

(56)

—H —Ph

(57)

—H

(58)

—H

(59)

—H

(60)

—H

(61)

—CH₂CH₃

(62)

—H

(63)

—H

(64)

—H

(65)

—H

(66)

—H

(67)

—H

(68)

—H

(69)

—H

(70)

—H

(71)

—H

(72)

—H

(73)

—H

(74)

—H

(75)

—H

(76)

—H

(77)

—H

(78)

—Ph —Ph

(79)

—CH₃ —Ph

(80)

—H —Ph

(81)

—CH₃ —Ph

(82)

—CH₂CH₃ —Ph

(83)

—CH₂CH₂CH₃ —Ph

(84)

—CH₂OCH₃ —Ph

(85)

—Ph —Ph

(86)

—Ph

(87)

—Ph

(88)

—Ph

(89)

—Ph

(90)

—Ph

(91)

—H —Ph

(92)

—H

(93)

—H

(94)

—H

(95)

—H

(96)

—H

(97)

—CH₂CH₃

(98)

—H

(99)

—H

(100)

—H

(101)

—H

(102)

—H

(103)

—H

(104)

—H

(105)

—H

(106)

—H

(107)

—H

(108)

—H

(109)

—H

(110)

—H

(111)

—H

(112)

—H

(113)

—H

(114)

—H

(115)

—H

Further representative species of the present invention are:Compounds (116)-(204) of the Formula B:

where R₁ and R₂ taken together to form R₁R₂, Rx and G are delineated foreach example in TABLE 3: TABLE 3 Compound Rx R₁R₂ G (116)

—OH (117)

—OH (118)

—OH (119)

—OH (120)

—OH (121)

—OH (122)

—OH (123)

—OH (124)

—OH (125)

—OH (126)

—OH (127)

—OH (128)

—OH (129)

—OH (130)

—OH (131)

—OH (132)

—OH (133)

—OH (134)

(135)

—OH (136)

—OH (137)

(138)

(139)

—OH (140)

(141)

(142)

—OH (143)

(144)

(145)

—OH (146)

(147)

—OH (148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

Further representative species of the present invention are:Compounds (205)-(208) of the Formula D:

W, Rx and G are delineated for each example in TABLE 4: TABLE 4 CompoundRx W G (205)

(206)

(207)

(208)

In one embodiment, the present invention features pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt, ester or prodrug thereof.

A further embodiment of the present invention includes pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds of thepresent invention, or a pharmaceutically acceptable salt, ester, orprodrug thereof, with a pharmaceutically acceptable carrier orexcipient.

In another embodiment, the pharmaceutical compositions of the presentinvention may further contain other anti-HCV agents. Examples ofanti-HCV agents include, but are not limited to, .alpha.-interferon,.beta.-interferon, ribavirin, and amantadine.

In another embodiment, the pharmaceutical compositions of the presentinvention may further contain other HCV protease inhibitors.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise inhibitor(s) of other targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, and internal ribosome entry site (IRES).

According to another embodiment, the present invention includes methodsof treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject a therapeutically effectiveamount of the pharmaceutical compounds or compositions of the presentinvention. The methods can further include administration of anadditional therapeutic agent, including another antiviral agent or ananti-HCV agent. The additional agent can be co-administered,concurrently administered or sequentially administered with a compound(a pharmaceutically acceptable salt, ester or prodrug thereof) or apharmaceutical composition of the present invention. The methods hereincan further include the step of identifying that the subject is in needof treatment for hepatitis C infection. The identification can be bysubjective (e.g., health care provider determination) or objective(e.g., diagnostic test) means.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, idenyl and the like.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclic(e.g. bi-, or tri-cyclic or more), fused or non-fused, aromatic radicalor ring having from five to ten ring atoms of which one or more ringatom is selected from, for example, S, O and N; zero, one or two ringatoms are additional heteroatoms independently selected from, forexample, S, O and N; and the remaining ring atoms are carbon, whereinany N or S contained within the ring may be optionally oxidized.Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “C₁-C₈ alkyl,” or “C₁-C₁₂ alkyl,” as used herein, refer tosaturated, straight- or branched-chain hydrocarbon radicals containingfrom one to eight, or from one to twelve carbon atoms, respectively.Examples of C₁-C₈ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl, heptyl and octyl radicals; and examples of C₁-C₁₂ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl,decyl, dodecyl radicals.

The term “C₂-C₈ alkenyl,” as used herein, denotes a monovalent groupderived from a hydrocarbon moiety containing from two to eight carbonatoms having at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, but are not limited to,for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl and the like.

The term “C₂-C₈ alkynyl,” as used herein, denotes a monovalent groupderived from a hydrocarbon moiety containing from two to eight carbonatoms having at least one carbon-carbon triple bond by the removal of asingle hydrogen atom. Representative alkynyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “C₃-C₈-cycloalkyl”, or “C₃-C₁₂-cycloalkyl,” as used herein,denotes a monovalent group derived from a monocyclic or polycyclicsaturated carbocyclic ring compound by the removal of a single hydrogenatom wherein said carbocyclic ring contains from 3 to 8, or from 3 to12, carbon atoms, respectively. Examples of C₃-C₈-cycloalkyl include,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopentyl and cyclooctyl; and examples of C₃-C₁₂-cycloalkyl include,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.

The term “C₃-C₈-cycloalkenyl”, or “C₃-C₁₂-cycloalkenyl” as used herein,denote a monovalent group derived from a monocyclic or polycycliccarbocyclic ring compound by the removal of a single hydrogen atomwherein said carbocyclic ring contains from 3 to 8, or from 3 to 12,carbon atoms, respectively, and has at least one carbon-carbon doublebond. Examples of C₃-C₈-cycloalkenyl include, but not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, and the like; and examples of C₃-C₁₂-cycloalkenyl include,but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

The terms “substituted” refer to independent replacement of one, two, orthree or more of the hydrogen atoms thereon with substituents including,but not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN,—NH₂, protected amino, —NH —C₁-C₁₂-alkyl, —NH —C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH —C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH— aryl, —OCONH— heteroaryl, —OCONH— heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)— heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂- aryl, —NHCO₂—heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂₋alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted. In some cases, each substituentin a substituted moiety is additionally optionally substituted with oneor more groups, each group being independently selected from —F, —Cl,—Br, —I, —OH, —NO₂, —CN, or —NH₂.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can be replaced with an aliphaticgroup, an alicyclic group or a heterocyclic group. An “aliphatic group”is non-aromatic moiety that may contain any combination of carbon atoms,hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, andoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may be used in placeof the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylenegroups described herein.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or polycyclic saturated carbocyclic ring compound bythe removal of a single hydrogen atom. Examples include, but not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be furthersubstituted.

The term “heterocyclic” as used herein, refers to a non-aromatic 5-, 6-or 7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, (iv) any ofthe above rings may be fused to a benzene ring, and (v) the remainingring atoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,[1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted to give substituted heterocyclic.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be divalent or trivalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkynylene, arylalkylene, hetoerarylalkylene andheterocycloalkylene groups are to be included in the above definitions,and are applicable to provide the formulas herein with proper valency.

The terms “halo” and “halogen,” as used herein, refers to an atomselected from fluorine, chlorine, bromine and iodine.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxy group sothat it will depart during synthetic procedures such as in asubstitution or elimination reactions. Examples of hydroxy activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxy activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxy protecting groups include benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al, Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, andindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of protogenic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans- isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately, by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of Formula I. Various forms of prodrugs are known in the art,for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxyysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof Powders and sprays can contain,in addition to the compounds of this invention, excipients such aslactose, talc, silicic acid, aluminum hydroxide, calcium silicates andpolyamide powder, or mixtures of these substances. Sprays canadditionally contain customary propellants such aschlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject, such as a human orother animal, by administering to the subject a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result. The term“therapeutically effective amount” of a compound of the invention, asused herein, means a sufficient amount of the compound so as to decreasethe viral load in a subject and/or decrease the subject's HCV symptoms.As is well understood in the medical arts a therapeutically effectiveamount of a compound of this invention will be at a reasonablebenefit/risk ratio applicable to any medical treatment.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or contemporaneously with the specific compound employed;and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.0 1 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

An additional method of the present invention is the treatment ofbiological samples with an inhibitory amount of a compound of thepresent invention in such amounts and for such time as is necessary toinhibit viral replication and/or reduce viral load. The term “inhibitoryamount” means a sufficient amount to inhibit viral replication and/ordecrease the hepatitis C viral load in a biological sample. The term“biological sample(s)” as used herein means a substance of biologicalorigin intended for administration to a subject. Examples of biologicalsamples include, but are not limited to blood and components thereofsuch as plasma, platelets, subpopulations of blood cells and the like;organs such as kidney, liver, heart, lung, and the like; sperm and ova;bone marrow and components thereof, or stem cells. Thus anotherembodiment of the present invention is a method of treating a biologicalsample by contacting said biological sample with an inhibitory amount ofa compound or pharmaceutical composition of the present invention.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

ABBREVIATIONS

Abbreviations which may appear in the following synthetic schemes andexamples are:

-   -   Ac for acetyl;    -   Boc for tert-butoxycarbonyl;    -   Bz for benzoyl;    -   Bn for benzyl;    -   CDI for carbonyldiimidazole;    -   dba for dibenzylidene acetone;    -   DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;    -   DIAD for diisopropylazodicarboxylate;    -   DMAP for dimethylaminopyridine;    -   DMF for dimethyl formamide;    -   DMSO for dimethyl sulfoxide;    -   dppb for diphenylphosphino butane;    -   EtOAc for ethyl acetate;    -   HATU for        2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate;    -   iPrOH for isopropanol;    -   NaHMDS for sodium bis(trimethylsilyl)amide;    -   NMO for N-methylmorpho line N-oxide;    -   MeOH for methanol;    -   Ph for phenyl;    -   POPd for dihydrogen        dichlorobis(di-tert-butylphosphino)palladium(II);    -   TBAHS for tetrabutyl ammonium hydrogen sulfate;    -   TEA for triethylamine;    -   THF for tetrahydrofuran;    -   TPP for triphenylphosphine;    -   Tris for Tris(hydroxymethyl)aminomethane;    -   BME for 2-mercaptoethanol;    -   BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium        hexafluorophosphate;    -   COD for cyclooctadiene;    -   DAST for diethylaminosulfur trifluoride;    -   DABCYL for        6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;    -   DCM for dichloromethane;    -   DIBAL-H for diisobutylaluminum hydride;    -   DIEA for diisopropyl ethylamine;    -   DME for ethylene glycol dimethyl ether;    -   DMEM for Dulbecco's Modified Eagles Media;    -   EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;    -   EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide        hydrochloride;    -   Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene)        (tricyclohexylphosphine)ruthenium(II);    -   KHMDS is potassium bis(trimethylsilyl) amide;    -   Ms for mesyl;    -   NMM for N-4-methylmorpholine;    -   PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;    -   RCM for ring-closing metathesis;    -   RT for reverse transcription;    -   RT-PCR for reverse transcription-polymerase chain reaction;    -   TEA for triethyl amine;    -   TFA for trifluoroacetic acid;    -   THF for tetrahydrofuran; and    -   TLC for thin layer chromatography.

SYNTHETIC METHODS

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

Scheme 1 describes the synthesis of intermediate Ig. The cyclic peptideprecursor Ig was synthesized from Boc-L-2-amino-8-nonenoic acid Ia andcis-L-hydroxyproline methyl ester Ib via steps A-D set forth generallyin Scheme 1. For further details of the synthetic methods employed toproduce the cyclic peptide precursor Ig, see U.S. Pat. No. 6,608,027,which is herein incorporated by reference in its entirety. Other aminoacid derivatives containing a terminal alkene may be used in place of Iain order to create varied macrocyclic structures (for further detailssee WO/0059929). Ring closure methathesis with a Ruthenium-basedcatalyst gave the desired key intermediate Ig (for further details onring closing metathesis see recent reviews: Grubbs et al., Acc. Chem.Res., 1995, 28, 446; Shrock et al., Tetrahedron 1999, 55, 8141;Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Tmka et al., Acc.Chem. Res. 2001, 34, 18; and Hoveyda et al., Chem. Eur. J. 2001, 7,945).

The analogs of the present invention were prepared via several differentsynthetic routes. The simplest method, shown in Scheme 2, is to condensecommercially available hydroxyphthalimide using Mitsunobu conditionsfollowed by deprotection of the phthalimide moiety with ammonia orhydrazine to provide hydroxy amine (2-2). For further details on theMitsunobu reaction, see O.

Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 29, 1-162(1983); D. L. Hughes, Organic Preparations and Procedures Int. 28,127-164 (1996); and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org.Chem. 1, 273-283 (1997). Alternatively, intermediate (2-2) can also bemade by converting hydroxy intermediate Ig to a suitable leaving groupsuch as, but not limited to OMs, OTs, OTf, bromide, or iodide; followedwith the deprotection of the phthalimide moiety with ammonia orhydrazine. Oximes (2-3) can be prepared by treating hydroxy amine withappropriate aldehyde or ketone optionally in the presence of an acid.Subsequent removal of the acid protecting group furnishes compounds offormula (2-4). A thorough discussion of solvents and conditions forprotecting the acid group can be found in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3^(rd) ed., John Wiley &Son, Inc, 1999.

The Scheme 3 describes the alternative methods to synthesize formula(3-2). The intermediates (3-1) can be made directly through Ig andoximes using Mitsunobu conditions. Or, intermediate (3-1) can also bemade through SN2 replacement of activated hydroxyl group by convertinghydroxy intermediate Ig to a suitable leaving group such as, but notlimited to OMs, OTs, OTf, bromide, or iodide. Subsequent removal of theacid protecting group furnishes compounds of formula (3-2).

Scheme 4 illustrates the modification of the N-terminal and C-teminal ofthe macrocycle. Deprotection of the Boc moiety with an acid, such as,but not limited to hydrochloric acid yields compounds of formula (4-2).The amino moiety of formula (4-2) can be alkylated or acylated withappropriate alkyl halide or acyl groups to give compounds of formula(4-3). Compounds of formula (4-3) can be hydrolyzed with base such aslithium hydroxide to free up the acid moiety of formula (4-4).Subsequent activation of the acid moiety followed by treatment withappropriate acyl or sulfonyl groups to provide compounds of formula(4-5).

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Example 1 Compound of Formula A, Wherein Rx=Boc and G=OEt

Step 1a.

To a solution of Boc-L-2-amino-8-nonenoic acid (1.36 g, 5 mol) and thecommercially available cis-L-hydroxyproline methyl ester (1.09 g, 6mmol) in 15 ml DMF, was added DIEA (4 ml, 4 eq.) and HATU (4 g, 2 eq).The coupling was carried out at 0° C. over a period of 1 hour. Thereaction mixture was diluted with 100 mL EtOAc, and followed by washingwith 5% citric acid 2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 ml and brine2×10 ml, respectively. The organic phase was dried over anhydrous Na₂SO₄and then was evaporated, affording the desired dipeptide (1.91 g, 95.8%)that was identified by HPLC (Retention time=8.9 min, 30-70%, 90% B), andMS.

MS (ESI): m/z=421.37 [M+Na].

Step 1b.

The dipeptide from step 1a (1.91 g) was dissolved in 15 mL of dioxaneand 15 mL of 1 N LiOH aqueous solution and the hydrolysis reaction wascarried out at RT for 4 hours. The reaction mixture was acidified by 5%citric acid and extracted with 100 mL EtOAc, and followed by washingwith water 2×20 ml, and brine 2×20 ml, respectively. The organic phasewas dried over anhydrous Na₂SO₄ and then removed in vacuum, yielding thefree carboxylic acid compound (1.79 g, 97%), which was used for nextstep synthesis without need for further purification.

Step 1c.

To a solution of the free acid obtained from step 1b (1.77, 4.64 mmol)in 5 ml DMF, D-β-vinyl cyclopropane amino acid ethyl ester 1e (0.95 g, 5mmol), DIEA (4 ml, 4 eq.) and HATU (4 g, 2 eq) were added. The couplingwas carried out at 0° C. over a period of 5 hours. The reaction mixturewas diluted with 80 mL EtOAc, and followed by washing with 5% citricacid 2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 ml and brine 2×10 ml,respectively. The organic phase was dried over anhydrous Na₂SO₄ and thenevaporated. The residue was purified by silica gel flash chromatographyusing different ratios of hexanes:EtOAc as elution phase(5:1→3:1→1:1→1:2→1:5). The desired linear tripeptide was isolated as anoil after removal of the elution solvents (1.59 g, 65.4%).

MS (ESI): m/z=544.84 [M+Na].

Step 1d.

A solution of the linear tripeptide from step 1c (1.51 g, 2.89 mmol) in200 ml dry DCM was deoxygenated by bubbling N₂. Hoveyda's 1^(st)generation catalyst (5 mol % eq.) was then added as solid. The reactionwas refluxed under N₂ atmosphere 12 hours. The solvent was evaporatedand the residue was purified by silica gel flash chromatography usingdifferent ratios of hexanes:EtOAc as elution phase(9:1→5:1→3:1→1:1→1:2→1:5). The cyclic peptide precursor 1 was isolatedas a white powder after removal of the elution solvents (1.24 g, 87%).For further details of the synthetic methods employed to produce thecyclic peptide precursor 1, see U.S. Pat. No. 6,608,027, which is hereinincorporated by reference in its entirety.

MS (ESI): m/z=516.28 [M+Na].

Step 1e.

To a solution of the cyclic precursor from step 1d 200 mg,N-hydroxylphthalamide (80 mg) and PPh₃ (163 mg) in THF was added DIAD(102 μL) at 0° C. The reaction mixture was stirred for overnight at roomtemperature. The mixture was then concentrated and purified by silicagel chromatography to give 325 mg of desired product.

MS (ESI): m/z=639.29 [M+H].

Step 1f.

To a solution of compound from step 1e (50 mg) in 1 ml EtOH was addedNH₂NH₂ (5 eq) The reaction mixture was stirred for 30 min at roomtemperature. The mixture was then concentrated and extracted with DCM.The organic extracts were washed with 1M NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated. The residue was carried directly forthe next step without further purification.

MS (ESI): m/z=509.37 [M+H].

Example 2 Compound of Formula A, Wherein Rx=Cyclopentyloxycarbonyl andG=OEt

Step 2a.

To a flask containing the compound from step 1e (1.22 mmol) was added 4NHCl/dioxane (10 ml). The resulting mixture was stirred for 1 hr at roomtemperature. The mixture was then concentrated. The residue wasprecipitated with MTBE. The precipitates was filtered and washed withMTBE to give desired product.

MS (ESI): m/z=539.14 [M+H].

Step 2b.

To a solution of the compound from step 2a (1.22 mmol) in DCM was addedDIEA (2.2 ml) and cyclopentylchloroformate (3 eq) at 0° C. The mixturewas stirred for 1.5 h at room temperature. The reaction mixture wasextracted with EtOAc. The organic extracts were washed with NaHCO₃,brine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by silica gel chromatography to give 850 mg of desiredproduct.

MS (ESI): m/z=651.21 [M+H].

Step 2c.

To a solution of compound from step 2b of Example 2 (0.41 mmol)) in EtOHwas added NH₂NH₂ (80 μL)). The reaction mixture was stirred for 45 minat room temperature. The mixture was then concentrated and extractedwith DCM. The organic extracts were washed with 1M NaHCO₃, brine, driedover Na₂SO₄, filtered and concentrated. The residue was carried directlyfor the next step without further purification.

MS (ESI): m/z=521.23 [M+H].

Example 3 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Methyl, R₂=Phenyl and G=OH

Step 3a.

The mixture of compound from step 2c of Example 2 (0.05 mmol),acetophenone (0.1 mmol), HOAc (0.2 mmol) and pyridine (0.1 mmol) in EtOHwas stirred at 60° C. overnight. The reaction mixture was extracted withEtOAc. The organic extracts were washed with 1M NaHCO3, brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography to give desired product.

Step 3b.

To a solution of the compound from step 3a in THF/MeOH was added 1NLiOH.The reaction mixture was stirred overnight at room temperature. Afteracidified with 1NHCl, the resulting mixture was extracted with EtOAc.The organic extracts were washed with water and concentrated. Theresidue was purified by preparative HPLC to give desired product.

MS (ESI): m/z=595.24 [M+H].

Example 4 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Ethyl, R₂=Phenyl and G=OH

Step 4a.

The title compound was prepared with compound from step 2c of Example 2and propiophenone via the similar conditions described in step 3a ofExample-3.

MS (ESI): m/z=637.27 [M+H].

Step 4b.

The title compound was prepared with compound from step 4a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=609.26 [M+H].

Example 5 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Propyl, Rz=Phenyl and G=OH

Step 5a.

The title compound was prepared with compound from step 2c of Example 2and n-Butylphenone via the similar conditions described in step 3a ofExample-3.

MS (ESI): m/z=651.36 [M+H].

Step 5b.

The title compound was prepared with compound from step 5a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=623.32 [M+H].

Example 6 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=CH₃OCH₂, R₂=Phenyl and G=OH

Step 6a.

The title compound was prepared with compound from step 2c of Example 2and 2-Methoxy-acetophenone via the similar conditions described in step3a of Example-3.

MS (ESI): m/z=653.33[M+H].

Step 6b.

The title compound was prepared with compound from step 6a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=625.24 [M+H].

Example 7 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Phenyl, R₂=Phenyl and G=OH

Step 7a.

The title compound was prepared with compound from step 2c of Example 2and benzophenone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=685.20 [M+H].

Step 7b.

The title compound was prepared with compound from step 7a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=657.24 [M+H].

Example 8 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Thiophen-2-yl, R₂=Phenyl and G=OH

Step 8a.

The title compound was prepared with compound from step 2c of Example 2and 2-Benzoylthiophene via the similar conditions described in step 3aof Example-3.

MS (ESI): m/z=691.16 [M+H].

Step 8b.

The title compound was prepared with compound from step 8a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=663.19 [M+H].

Example 9 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Isopropyl, R₂=Phenyl and G=OH

Step 9a.

The title compound was prepared with compound from step 2c of Example 2and isobutyrophenone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=651.32 [M+H].

Step 9b.

The title compound was prepared with compound from step 9a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=623.25 [M+H].

Example 10 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=2-Methyl-Propan-1-yl, R₂=Phenyl and G=OH

Step 10a.

The title compound was prepared with compound from step 2c of Example 2and isovalerophenone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=665.34 [M+H].

Step 10b.

The title compound was prepared with compound from step 10a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=637.27 [M+H].

Example 11 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Cyclopentyl, R₂=Phenyl and G=OH

Step 11a.

The title compound was prepared with compound from step 2c of Example 2and Cyclopentyl phenyl ketone via the similar conditions described instep 3a of Example-3.

MS (ESI): m/z=677.32 [M+H].

Step 11b.

The title compound was prepared with compound from step 11a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=649.28 [M+H].

Example 12 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Cyclohexyl, R₂=Phenyl and G=OH

Step 12a.

The title compound was prepared with compound from step 2c of Example 2and Cyclohexyl phenyl ketone via the similar conditions described instep 3a of Example-3.

MS (ESI): m/z=691.38 [M+H].

Step 12b.

The title compound was prepared with compound from step 12a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=663.28 [M+H].

Example 13 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Phenyl and G=OH

Step 13a.

The title compound was prepared with compound from step 2c of Example 2and benzaldehyde via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=609 [M+H].

Step 13b.

The title compound was prepared with compound from step 13a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=581.31 [M+H].

Example 14 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Biphenyl-2-yl and G=OH

Step 14a.

The title compound was prepared with compound from step 2c of Example 2and Biphenyl-2-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 14b.

The title compound was prepared with compound from step 14a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=657.24 [M+H].

Example 15 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Biphenyl-3-yl and G=OH

Step 15a.

The title compound was prepared with compound from step 2c of Example 2and Biphenyl-3-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 15b.

The title compound was prepared with compound from step 15a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=657.30 [M+H].

Example 16 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Biphenyl-4-yl and G=OH

Step 16a.

The title compound was prepared with compound from step 2c of Example 2and Biphenyl-4-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 16b.

The title compound was prepared with compound from step 1 6a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=657.24 [M+H].

Example 17 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Naphthalen-1-yl and G=OH

Step 17a.

The title compound was prepared with compound from step 2c of Example 2and Naphthalene-1-carboxaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=659.21 [M+H].

Step 17b.

The title compound was prepared with compound from step 17a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=631.26 [M+H].

Example 18 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Naphthalen-2-yl and G=OH

Step 18a.

The title compound was prepared with compound from step 2c of Example 2and Naphthalene-2-carboxaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=659.21 [M+H].

Step 18b.

The title compound was prepared with compound from step 18a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=631.26 [M+H].

Example 19 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=Ethyl R₂=Biphenyl-2-yl and G=OH

Step 19a.

The title compound was prepared with compound from step 2c of Example 2and 1-Biphenyl-2-yl-propan-3-one via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=713 [M+H].

Step 19b.

The title compound was prepared with compound from step 19a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=685.21 [M+H].

Example 20 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=Pyridin-2-yl and G=OH

Step 20a.

The title compound was prepared with compound from step 2c of Example 2and Pyridine-2-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 20b.

The title compound was prepared with compound from step 20a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=582.23 [M+H].

Example 21 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=Pyridin-3-yl and G=OH

Step 21a.

The title compound was prepared with compound from step 2c of Example 2and Pyridine-3-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 21b.

The title compound was prepared with compound from step 21a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=582.23 [M+H].

Example 22 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Pyridin-4-yl and G=OH

Step 22a.

The title compound was prepared with compound from step 2c of Example 2and Pyridine-4-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 22b.

The title compound was prepared with compound from step 22a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=582.24 [M+H].

Example 23 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Quinolin-4-yl and G=OH

Step 23a.

The title compound was prepared with compound from step 2c of Example 2and Quinoline-4-carboxaldehyde via the similar conditions described instep 3a of Example 3.

Step 23b.

The title compound was prepared with compound from step 23a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=632.22 [M+H].

Example 24 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Quinolin-3-yl and G=OH

Step 24a.

The title compound was prepared with compound from step 2c of Example 2and Quinoline-3-carboxaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=660.20 [M+H].

Step 24b.

The title compound was prepared with compound from step 24a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=632.22 [M+H].

Example 25 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(2-Methoxy-phenyl) and G=OH

Step 25a.

The title compound was prepared with compound from step 2c of Example 2and 2-Methoxy-benzaldehyde via the similar conditions described in step3a of Example 3.

Step 25b.

The title compound was prepared with compound from step 25a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=611.27 [M+H].

Example 26 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(3-Methoxy-phenyl) and G=OH

Step 26a.

The title compound was prepared with compound from step 2c of Example 2and 3-Methoxy-benzaldehyde via the similar conditions described in step3a of Example 3.

Step 26b.

The title compound was prepared with compound from step 26a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=611.27 [M+H].

Example 27 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(4-Methoxy-phenyl) and G=OH

Step 27a.

The title compound was prepared with compound from step 2c of Example 2and 4-Methoxy-benzaldehyde via the similar conditions described in step3a of Example 3.

Step 27b.

The title compound was prepared with compound from step 27a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=611.25 [M+H].

Example 28 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(2-Fluoro-phenyl) and G=OH

Step 28a.

The title compound was prepared with compound from step 2c of Example 2and 2-Fluoro-benzaldehyde via the similar conditions described in step3a of Example 3.

Step 28b.

The title compound was prepared with compound from step 28a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=599.21 [M+H].

Example 29 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(3-Fluoro-phenyl) and G=OH

Step 29a.

The title compound was prepared with compound from step 2c of Example 2and 3-Fluoro-benzaldehyde via the similar conditions described in step3a of Example-3.

Step 29b.

The title compound was prepared with compound from step 29a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=599.27 [M+H].

Example 30 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(4-Fluoro-phenyl) and G=OH

Step 30a.

The title compound was prepared with compound from step 2c of Example 2and 4-Fluoro-benzaldehyde via the similar conditions described in step3a of Example 3.

Step 30b.

The title compound was prepared with compound from step 30a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=599.25 [M+H].

Example 31 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Thiophen-2-yl-phenyl) and G=OH

Step 31a.

The title compound was prepared with compound from step 2c of Example 2and 2-Thiophen-2-yl-benzaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z 691.24 [M+H].

Step 31b.

The title compound was prepared with compound from step 31a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=662.79 [M+H].

Example 32 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Pyrazol-1-yl-phenyl) and G=OH

Step 32a.

The title compound was prepared with compound from step 2c of Example 2and 2-Pyrazol-1-yl-benzaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=675.27 [M+H].

Step 32b.

The title compound was prepared with compound from step 32a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=647.14 [M+H].

Example 33 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-[1 2,4]Triazol- 1-yl-phenyl) and G=OH

Step 33a.

The title compound was prepared with compound from step 2c of Example 2and 2-[1,2,4]Triazol-1-yl-benzaldehyde via the similar conditionsdescribed in step 3a of Example 3.

MS (ESI): m/z=676.18 [M+H].

Step 33b.

The title compound was prepared with compound from step 33a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=648.30 [M+H].

Example 34 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Thiazol-2-yl-phenyl) and G=OH

Step 34a.

The title compound was prepared with compound from step 2c of Example 2and 2-Thiazol-2-yl-benzaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=692.14 [M+H].

Step 34b.

The title compound was prepared with compound from step 34a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=664.27 [M+H].

Example 35 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Imidazol-1-yl-phenyl) and G=OH

Step 35a.

The title compound was prepared with compound from step 2c of Example 2and 2-Imidazol-1-yl-benzaldehyde via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=675.19 [M+H].

Step 35b.

The title compound was prepared with compound from step 35a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=647.29 [M+H].

Example 36 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(5-Methoxy-2-thiophen-2-yl-phenyl) and G=OH

Step 36a.

The title compound was prepared with compound from step 2c of Example 2and 5-Methoxy-2-thiophen-2-yl-benzaldehyde via the similar conditionsdescribed in step 3a of Example 3.

MS (ESI): m/z=721.28 [M+H].

Step 36b.

The title compound was prepared with compound from step 36a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=693.20 [M+H].

Example 37 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(5-Methoxy-2-thiazol-2-yl-phenyl) and G=OH

Step 37a.

The title compound was prepared with compound from step 2c of Example 2and 5-Methoxy-2-thiazol-2-yl-benzaldehyde via the similar conditionsdescribed in step 3a of Example 3.

MS (ESI): m/z=722.27 [M+H].

Step 37b.

The title compound was prepared with compound from step 37a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=694.32 [M+H].

Example 38 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=(5-Methoxy-2-thiophen-2-yl-phenyl) and G=NHSO₂-cyclopropyl

To a solution of compound from step 36b of Example 36 in DMF was addedCDI. The reaction mixture was stirred at 40° C. for 1 h and then addedcyclopropylsulfonamide and DBU. The reaction mixture was stirredovernight at 40° C. The reaction mixture was extracted with EtOAc. Theorganic extracts were washed with 1M NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatograph to give desired product.

MS (ESI): m/z=796.21 [M+H].

Example 39 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁═H, R₂=Biphenyl-2-yl and G=NHSO₂-cyclopropyl

To a solution of compound from step 14b of Example 14 in DMF was addedCDI. The reaction mixture was stirred at 40° C. for 1 h and then addedcyclopropylsulfonamide and DBU. The reaction mixture was stirredovernight at 40° C. The reaction mixture was extracted with EtOAc. Theorganic extracts were washed with 1M NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatograph to give desired product.

MS (ESI): m/z=760.35 [M+H].

Example 40 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Thiophen-2-yl-phenyl) and G=NHSO₂-cyclopropyl

To a solution of compound from step 31b of Example 31 in DMF was addedCDI. The reaction mixture was stirred at 40° C. for 1 h and then addedcyclopropylsulfonamide and DBU. The reaction mixture was stirredovernight at 40° C. The reaction mixture was extracted with EtOAc. Theorganic extracts were washed with 1M NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatograph to give desired product.

MS (ESI): m/z=766.34 [M+H].

Example 41 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Isoxazol-5-yl-5-methoxy-phenyl) and G=OH

Step 41a.

The title compound was prepared with compound from step 2c of Example 2and 2-Isoxazol-5-yl-5-methoxy-benzaldehyde via the similar conditionsdescribed in step 3a of Example 3.

MS (ESI): m/z=706.50 [M+H].

Step 41b.

The title compound was prepared with compound from step 41 a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=678.33 [M+H].

Example 42 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl,R₁=H, R₂=(2-Isoxazol-5-yl-5-methoxy-phenyl) and G=NHSO₂-cyclopropyl

To a solution of compound from step 41b of Example 41 in DMF was addedCDI. The reaction mixture was stirred at 40° C. for 1 h and then addedcyclopropylsulfonamide and DBU. The reaction mixture was stirredovernight at 40° C. The reaction mixture was extracted with EtOAc. Theorganic extracts were washed with 1M NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatograph to give desired product.

MS (ESI): m/z=781.22 [M+H].

Example 43 Compound of Formula B, Wherein Rx=Boc, R₁=Phenyl R₂=Phenyland G=OH

Step 43a.

The title compound was prepared with compound from step 1f of Example 1and benzophenone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=673.46 [M+H].

Step 43b.

The title compound was prepared with compound from step 43a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=645.06 [M+H].

Example 44 Compound of Formula B, Wherein Rx=Boc, R₁=CH, R₂=Phenyl andG=OH

Step 44a.

The title compound was prepared with compound from step 1f of Example 1and acetophenone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=611.35 [M+H].

Step 44b.

The title compound was prepared with compound from step 44a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=583.31 [M+H].

Example 45 Compound of Formula B, Wherein Rx=Boc, R₁═H, R₂=Phenyl andG=OH

Step 45a.

The title compound was prepared with compound from step 1f of Example 1and benzaldehyde via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=597.35 [M+H].

Step 45b.

The title compound was prepared with compound from step 45a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=569.26 [M+H].

Example 46 to Example 115 (Formula B) are made following the proceduresdescribed in Examples 1, 3 or 38. (B)

Compound Rx R₁ R₂ G (46)

—CH₃ —Ph

(47)

—CH₂CH₃ —Ph

(48)

—CH₂CH₂CH₃ —Ph

(49)

—CH₂OCH₃ —Ph

(50)

—Ph —Ph

(51)

—Ph

(52)

—Ph

(53)

—Ph

(54)

—Ph

(55)

—Ph

(56)

—H —Ph

(57)

—H

(58)

—H

(59)

—H

(60)

—H

(61)

—CH₂CH₃

(62)

—H

(63)

—H

(64)

—H

(65)

—H

(66)

—H

(67)

—H

(68)

—H

(69)

—H

(70)

—H

(71)

—H

(72)

—H

(73)

—H

(74)

—H

(75)

—H

(76)

—H

(77)

—H

(78)

—Ph —Ph

(79)

—CH₃ —Ph

(80)

—H —Ph

(81)

—CH₃ —Ph

(82)

—CH₂CH₃ —Ph

(83)

—CH₂CH₂CH₃ —Ph

(84)

—CH₂OCH₃ —Ph

(85)

—Ph —Ph

(86)

—Ph

(87)

—Ph

(88)

—Ph

(89)

—Ph

(90)

—Ph

(91)

—H —Ph

(92)

—H

(93)

—H

(94)

—H

(95)

—H

(96)

—H

(97)

—CH₂CH₃

(98)

—H

(99)

—H

(100)

—H

(101)

—H

(102)

—H

(103)

—H

(104)

—H

(105)

—H

(106)

—H

(107)

—H

(108)

—H

(109)

—H

(110)

—H

(111)

—H

(112)

—H

(113)

—H

(114)

—H

(115)

—H

Example 116 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 116a.

The title compound was prepared with compound from step 2c of Example 2and 9-Fluorenone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z 683.20 [M+H].

Step 116b.

The title compound was prepared with compound from step 116a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=655.20 [M+H].

Example 117 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 117a.

The title compound was prepared with compound from step 2c of Example 2and 1,8-Diazafluoren-9-one via the similar conditions described in step3a of Example 3.

MS (ESI): m/z=685.20 [M+H].

Step 117b.

The title compound was prepared with compound from step 117a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=657.21 [M+H].

Example 118 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 118a.

The title compound was prepared with compound from step 2c of Example 2and 4,5-Diazafluoren-9-one via the similar conditions described in step3a of Example 3.

MS (ESI): m/z=685.30 [M+H].

Step 118b.

The title compound was prepared with compound from step 118a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=657.33 [M+H].

Example 119 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 119a.

The title compound was prepared with compound from step 2c of Example 2and 10-Methyl-10H-acridin-9-one via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z 712.40 [M+H].

Step 119b.

The title compound was prepared with compound from step 119a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=684.22 [M+H].

Example 120 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 120a.

The title compound was prepared with compound from step 2c of Example 2and Anthraquinone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=711.27 [M+H].

Step 120b.

The title compound was prepared with compound from step 120a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=683.26 [M+H].

Example 121 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 121a.

The title compound was prepared with compound from step 2c of Example 2and Dibenzosuberone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=711.32 [M+H].

Step 121b.

The title compound was prepared with compound from step 121a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=683.23 [M+H].

Example 122 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 122a.

The title compound was prepared with compound from step 2c of Example 2and Indan-1-one via the similar conditions described in step 3a ofExample 3.

Step 122b.

The title compound was prepared with compound from step 122a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=607.23 [M+H].

Example 123 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 123a.

The title compound was prepared with compound from step 2c of Example 2and 1-Tetralone via the similar conditions described in step 3a ofExample 3.

Step 123b.

The title compound was prepared with compound from step 123a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=621.24 [M+H].

Example 124 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 124a.

The title compound was prepared with compound from step 2c of Example 2and 6-Methoxy-1-tetralone via the similar conditions described in step3a of Example 3.

MS (ESI): m/z=679.22 [M+H].

Step 124b.

The title compound was prepared with compound from step 124a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=651.29 [M+H].

Example 125 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 125a.

The title compound was prepared with compound from step 2c of Example 2and 7-Methoxy-1-tetralone via the similar conditions described in step3a of Example 3.

MS (ESI): m/z=679.22 [M+H].

Step 125b.

The title compound was prepared with compound from step 125a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=651.29 [M+H].

Example 126 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 126a.

The title compound was prepared with compound from step 2c of Example 2and 6,7-Dimethoxy-1-tetralone via the similar conditions described instep 3a of Example 3.

MS (ESI): m/z=709.22 [M+H].

Step 126b.

The title compound was prepared with compound from step 126a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=681.30 [M+H].

Example 127 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 127a.

The title compound was prepared with compound from step 2c of Example 2and 5,6,7,8-Tetrahydroquinolinone-5 via the similar conditions describedin step 3a of Example-3.

MS (ESI): m/z=650.23 [M+H].

Step 127b.

The title compound was prepared with compound from step 127a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=622.29 [M+H].

Example 128 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 128a.

The title compound was prepared with compound from step 2c of Example 2and Thiochroman-4-one via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=667.18 [M+H].

Step 128b.

The title compound was prepared with compound from step 128a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=639.23 [M+H].

Example 129 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 129a.

The title compound was prepared with compound from step 2c of Example 2and Chroman-4-one via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=651.31 [M+H].

Step 129b.

The title compound was prepared with compound from step 129a via thesimilar conditions described in step 3b of Example-3.

MS (ESI): m/z=623.36 [M+H].

Example 130 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 130a.

The title compound was prepared with compound from step 2c of Example 2and 6-Methoxy-chroman-4-one via the similar conditions described in step3a of Example 3.

MS (ESI): m/z=681.21[M+H].

Step 130b.

The title compound was prepared with compound from step 130a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=653.24 [M+H].

Example 131 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 131a.

The title compound was prepared with compound from step 2c of Example 2and 6,7-Dimethoxy-2,2-dimethyl-chroman-4-one via the similar conditionsdescribed in step 3a of Example 3.

MS (ESI): m/z=739.32 [M+H].

Step 131b.

The title compound was prepared with compound from step 131 a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=711.31 [M+H].

Example 132 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 132a.

The title compound was prepared with compound from step 2c of Example 2and 6,7-dihydro-5H-quinolin-8-one via the similar conditions describedin step 3a of Example 3.

MS (ESI): m/z=650.21 [M+H].

Step 132b.

The title compound was prepared with compound from step 132a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=622.23 [M+H].

Example 133 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

Step 133a.

The title compound was prepared with compound from step 2c of Example 2and 7-Thiophen-2-yl-3,4-dihydro-2H-naphthalen-1-one via the similarconditions described in step 3a of Example 3.

MS (ESI): m/z=731.28 [M+H].

Step 133b.

The title compound was prepared with compound from step 133a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=703.21 [M+H].

Example 134 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

To a solution of compound from step 116b of Example 116 in DMF was addedCDI. The reaction mixture was stirred at 40° C. for 1 h and then addedcyclopropylsulfonamide and DBU. The reaction mixture was stirredovernight at 40° C. The reaction mixture was extracted with EtOAc. Theorganic extracts were washed with 1M NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatograph to give desired product.

MS (ESI): m/z=758.14 [M+H].

Example 135 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=OH

Step 135a.

The title compound was prepared with compound from step 1f of Example 1and 1-indanone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=623.34 [M+H].

Step 135b.

The title compound was prepared with compound from step 135a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=595.32 [M+H].

Example 136 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=OH

Step 136a.

The title compound was prepared with compound from step 1f of Example 1and 1-tetralone via the similar conditions described in step 3a ofExample 3.

MS (ESI): m/z=637.45 [M+H].

Step 136b.

The title compound was prepared with compound from step 136a via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=609.34 [M+H].

Example 137 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

To a solution of compound from step 117b of Example 117 in DMF was addedCDI. The reaction mixture was stirred at 40° C. for 1 h and then addedcyclopropylsulfonamide and DBU. The reaction mixture was stirredovernight at 40° C. The reaction mixture was extracted with EtOAc. Theorganic extracts were washed with 1M NaHCO₃, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatograph to give desired product.

MS (ESI): m/z=760.18 [M+H].

Example 138 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

To a solution of compound from step 116b of Example 116 in DMF was addedHATU and DIEA. The reaction mixture was stirred at 40° C. for 20 min andthen added 5-aminotetrazole. The reaction mixture was stirred overnightat 90° C. The reaction mixture was directly purified by HPLC to givedesired product.

MS (ESI): m/z=722.31 [M+H].

Example 139 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=OH

Step 139a.

The mixture of xanthone (1.0 g), hydroxylamine hydrochloride (1.77 g)and pyridine (12 ml) was heated to 110° C. for 2days. The reactionmixture was concentrated and the residue was extracted with EtOAc. Theorganic layer was washed with 1% HCl, water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatography to give desired product.

MS (ESI): m/z=212.08 [M+H].

Step 139b.

To a solution of the macrocyclic peptide precursor from step 1d ofExample 1 (500 mg, 1.01 mmol) and DIEA (0.4 ml, 2 mmol) in 2.0 ml DCM,mesylate chloride (0.1 ml) was added slowly at 0° C. where the reactionwas kept for 3 hours. 30 mL EtOAc was then added and followed by washingwith 5% citric acid 2×10 ml, water 2×10 ml, 1M NaHCO₃ 2×10 ml and brine2×10 ml, respectively. The organic phase was dried over anhydrous Na₂SO₄and evaporated, yielding the title compound mesylate that was used fornext step synthesis without need for further purification.

MS (ESI): m/z=572.34 [M+H].

Step 139c.

To a solution of the mesylate from step 139b (50 mg) in 2 mL DMF, wasadded 37 mg of the oxime from step 139a and anhydrous sodium carbonate(86 mg). The resulting reaction mixture was stirred vigorously at 60° C.for 12 hours. The reaction mixture was extracted with EtOAc. The organiclayer was washed with 1M NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatography to give 22 mg of desired product.

MS (ESI): m/z=687.39 [M+H].

Step 139d.

The title compound was prepared with compound from step 139c via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=659.33 [M+H].

Example 140 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=NHSO₂-cyclopropyl

The title compound was prepared with compound from step 139d via thesimilar conditions described in Example 134.

MS (ESI): m/z=762.21 [M+H].

Example 141 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

Step 141a.

The solution of the compound from Example 140 in 5 ml 4NHCl/Dioxne wasstirred at RT for 1 h. The reaction mixture was concentrated in vacuum.The residue was evaporated twice with DCM. The desired product wascarried out directly to the next step.

MS (ESI): m/z=662.19 [M+H].

Step 141b.

To the solution of the compound from Example 141a in 2 ml DCM was addedDIEA (0.32 mmol) and cyclopentylchloroformate (0.096 mmol). The reactionmixture was stirred at RT for 1 h. The reaction mixture was extractedwith EtOAc. The organic layer was washed with 1M NaHCO₃, water, brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby HPLC to give 16 mg of desired product.

MS (ESI): m/z=774.31 [M+H].

13C(CD3OD): 178.2, 173.5, 169.4, 156.6, 152.9, 151.4, 141.1, 135.6,131.9, 131.6, 130.7, 124.9, 124.6, 123.6, 122.8, 119.1, 117.1, 116.5,116.2, 83.0, 77.4, 59.8, 53.1, 52.5, 43.9, 34.4, 32.4, 32.3, 30.7, 29.9,27.4, 27.1, 26.5, 23.2, 22.0, 21.0.

Example 142 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=OH

Step 142a.

The oxime was prepared with flavanone via the similar conditionsdescribed in step 139a of Example 139.

MS (ESI): m/z=238.10 [M+H].

Step 142b.

To a solution of the cyclic precursor from step 1d 100 mg, oxime fromstep 142a (71 mg) and PPh₃ (105 mg) in THF was added DEAD (63 μL) at 0°C. The reaction mixture was stirred for overnight at room temperature.The mixture was then concentrated and purified by silica gelchromatography to give desired product.

MS (ESI): m/z=713.40 [M+H].

Step 142c.

The title compound was prepared with compound from step 142b via thesimilar conditions described in step 3b of Example 3.

MS (ESI): m/z=685.25 [M+H].

Example 143 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=NHSO₂-cyclopropyl

The title compound was prepared with compound from step 142c of Example142 via the similar conditions described in Example 134.

MS (ESI): m/z=788.37 [M+H].

Example 144 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

The title compound was prepared with compound from Example 143 via thesimilar conditions described in Example 141.

MS (ESI): m/z=800.39 [M+H].

13C (CD3OD): 177.5, 173.8, 169.3, 166.4, 163.4, 157.1, 153.6, 135.6,131.6, 129.9, 129.1, 129.0, 127.6, 126.9, 124.9, 121.7, 117.7, 114.0,101.4, 77.7, 76.9, 59.5, 53.7, 52.9, 43.6, 34.5, 32.7, 31.8, 30.6, 30.0,27.5, 27.4, 26.6, 23.2, 22.1, 20.9.

Example 145 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=OH

The title compound was prepared with isofalavanone via the similarconditions described in Example 142.

MS (ESI): m/z=685.20 [M+H].

Example 146 Compound of Formula B, Wherein Rx=Boc, R₁ and R₂ TakenTogether with the Carbon Atom to Which They are Attached are

and G=NHSO0-cyclopropyl

The title compound was prepared with compound from Example 145 via thesimilar conditions described in Example 134.

MS (ESI): m/z=788.29 [M+H].

13C (CD3OD): 177.7, 173.3, 169.4, 165.7, 156.8, 154.4, 135.3, 132.8,121.9, 131.0, 128.4, 128.1, 127.7, 126.8, 126.1, 125.0, 121.1, 120.5,113.4, 90.4, 79.9, 76.3, 59.7, 52.5, 52.4, 43.6, 35.0, 32.2, 30.6, 30.1,27.5, 27.3, 26.4, 21.7, 21.1.

Example 147 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=OH

The title compound was prepared with 6-fluoro-4-chromanone via thesimilar conditions described in Example 3.

MS (ESI): m/z=641.26 [M+H].

Example 148 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

The title compound was prepared with compound from Example 147 via thesimilar conditions described in Example 134.

MS (ESI): m/z=744.36 [M+H].

13C (CD3OD): 176.9, 174.0, 168.1, 158.2, 156.3, 156.0, 152.9, 149.9,136.3, 124.4, 118.9, 118.8, 118.5, 118.3, 110.1, 109.9, 81.3, 78.4,65.0, 60.0, 53.4, 52.4, 44.4, 34.1, 32.6, 32.5, 31.0, 29.8, 27.1, 26.9,26.0, 23.9, 23.5, 23.4, 22.0, 20.8.

Example 149 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

The title compound was prepared with compound from Example 125 via thesimilar conditions described in Example 134.

MS (ESI): m/z=754.39 [M+H].

13C (CD3OD): 176.9, 174.1, 168.2, 157.9, 156.2, 136.3, 132.5, 130.9,129.6, 124.2, 116.9, 107.7, 80.8, 78.6, 60.2, 55.4, 53.6, 52.4, 44.3,34.4, 32.6, 32.5, 31.0, 29.8, 28.8, 27.2, 26.9, 26.0, 24.3, 23.5, 23.4,21.9, 21.5, 20.8.

Example 150 Compound of Formula B, Wherein Rx=Cyclopentyloxycarbonyl, R₁and R₂ Taken Together with the Carbon Atom to Which They are Attachedare

and G=NHSO₂-cyclopropyl

The title compound was prepared with compound from Example 130 via thesimilar conditions described in Example 134.

MS (ESI): m/z=756.35 [M+H].

13C (CD3OD): 177.1, 173.5, 168.1, 155.8, 153.9, 151.2, 150.5, 136.2,124.4, 119.5, 118.6, 118.1, 106.4, 81.2, 78.1, 65.0, 59.9, 55.7, 53.3,52.3, 44.4, 34.2, 32.7, 32.6, 32.5, 31.0, 29.7, 27.2, 26.0, 24.2, 23.5,23.4, 22.0, 20.8.

Example 151 to Example 186 (Formula B) are Made Following the ProceduresDescribed in Examples 1, 3, 134 or 141

(B)

Compound Rx R₁R₂ G (151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

The compounds of the present invention exhibit potent inhibitoryproperties against the HCV NS3 protease. The following examples describeassays in which the compounds of the present invention can be tested foranti-HCV effects.

Example 187 NS3/NS4a Protease Enzyme Assay

HCV protease activity and inhibition is assayed using an internallyquenched fluorogenic substrate. A DABCYL and an EDANS group are attachedto opposite ends of a short peptide. Quenching of the EDANS fluorescenceby the DABCYL group is relieved upon proteolytic cleavage. Fluorescenceis measured with a Molecular Devices Fluoromax (or equivalent) using anexcitation wavelength of 355 nm and an emission wavelength of 485 nm.

The assay is run in Corning white half-area 96-well plates (VWR29444-312 [Corning 3693]) with full-length NS3 HCV protease 1b tetheredwith NS4A cofactor (final enzyme concentration 1 to 15 nM). The assaybuffer is complemented with 10 μM NS4A cofactor Pep 4A (Anaspec 25336 orin-house, MW 1424.8). RET S1(Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser-Lys-(DABCYL)-NH₂,AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate.The assay buffer contains 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mMBME. The enzyme reaction is followed over a 30 minutes time course atroom temperature in the absence and presence of inhibitors.

The peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8)Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [−20° C.] and HCV Inh 2 (Anaspec 25346,MW 913.1) Ac-Asp-Glu-Dif-Cha-Cys-OH, are used as reference compounds.

IC50 values are calculated using XLFit in ActivityBase (IDBS) usingequation 205: y=A+((B-A)/(1+((C/x)ˆD))).

Example 188 Cell-Based Replicon Assay

Quantification of HCV replicon RNA (HCV Cell Based Assay) isaccomplished using the Huh 11-7 cell line (Lohmann, et al Science285:110-113, 1999). Cells are seeded at 4×10³ cells/well in 96 wellplates and fed media containing DMEM (high glucose), 10% fetal calfserum, penicillin-streptomycin and non-essential amino acids. Cells areincubated in a 7.5% C0₂ incubator at 37° C. At the end of the incubationperiod, total RNA is extracted and purified from cells using AmbionRNAqueous 96 Kit (Catalog No. AM1812). To amplify the HCV RNA so thatsufficient material can be detected by an HCV specific probe (below),primers specific for HCV (below) mediate both the reverse transcriptionof the HCV RNA and the amplification of the cDNA by polymerase chainreaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (AppliedBiosystems catalog no. 4309169). The nucleotide sequences of the RT-PCRprimers, which are located in the NS5B region of the HCV genome, are thefollowing:

HCV Forward primer “RBNS5bfor”

5′GCTGCGGCCTGTCGAGCT (SEQ ID NO: 1):

HCV Reverse primer “RBNS5Brev”

5′CAAGGTCGTCTCCGCATAC (SEQ ID NO 2).

Detection of the RT-PCR product is accomplished using the AppliedBiosystems (ABI) Prism 7500 Sequence Detection System (SDS) that detectsthe fluorescence that is emitted when the probe, which is labeled with afluorescence reporter dye and a quencher dye, is degraded during the PCRreaction. The increase in the amount of fluorescence is measured duringeach cycle of PCR and reflects the increasing amount of RT-PCR product.Specifically, quantification is based on the threshold cycle, where theamplification plot crosses a defined fluorescence threshold. Comparisonof the threshold cycles of the sample with a known standard provides ahighly sensitive measure of relative template concentration in differentsamples (ABI User Bulletin #2 Dec. 11, 1997). The data is analyzed usingthe ABI SDS program version 1.7. The relative template concentration canbe converted to RNA copy numbers by employing a standard curve of HCVRNA standards with known copy number (ABI User Bulletin #2 Dec. 11,1997).

The RT-PCR product was detected using the following labeled probe: (SEQID NO: 3) 5′ FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA

FAM=Fluorescence reporter dye.

TAMRA:=Quencher dye.

The RT reaction is performed at 48° C. for 30 minutes followed by PCR.Thermal cycler parameters used for the PCR reaction on the ABI Prism7500 Sequence Detection System are: one cycle at 95° C., 10 minutesfollowed by 40 cycles each of which include one incubation at 95° C. for15 seconds and a second incubation for 60° C. for 1 minute.

To normalize the data to an internal control molecule within thecellular RNA, RT-PCR is performed on the cellular messenger RNAglyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH copy numberis very stable in the cell lines used. GAPDH RT-PCR is performed on thesame RNA sample from which the HCV copy number is determined. The GAPDHprimers and probesare contained in the ABI Pre-Developed TaqMan AssayKit (catalog no. 4310884E). The ratio of HCV/GAPDH RNA is used tocalculate the activity of compounds evaluated for inhibition of HCV RNAreplication.

Activity of Compounds as Inhibitors of HCV Replication (Cell BasedAssay) in Replicon Containing Huh-7 Cell Lines.

The effect of a specific anti-viral compound on HCV replicon RNA levelsin Huh-11-7cells is determined by comparing the amount of HCV RNAnormalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cells exposedto compound versus cells exposed to the DMSO vehicle (negative control).Specifically, cells are seeded at 4×10³ cells/well in a 96 well plateand are incubated either with: 1) media containing 1% DMSO (0%inhibition control), or 2) media/1% DMSO containing a fixedconcentration of compound. 96 well plates as described above are thenincubated at 37° C. for 4 days (EC50 determination). Percent inhibitionis defined as:

% Inhibition=100−100*S/C1

where

S=the ratio of HCV RNA copy number/GAPDH RNA copy number in the sample;

C 1=the ratio of HCV RNA copy number/GAPDH RNA copy number in the 0%inhibition control (media/1% DMSO).

The dose-response curve of the inhibitor is generated by adding compoundin serial, three-fold dilutions over three logs to wells starting withthe highest concentration of a specific compound at 1.5 uM and endingwith the lowest concentration of 0.23 nM. Further dilution series (500nM to 0.08 nM for example) is performed if the EC50 value is notpositioned well on the curve. EC50 is determined with the IDBS ActivityBase program “XL Fit” using a 4-paramater, non-linear regression fit(model # 205 in version 4.2.1, build 16).

In the above assays, representative compounds of the present inventionare found to have HCV replication inhibitory activity and HCV NS3protease inhibitory activity. For instance, representative compounds offormulae III, IV, VIII and IX, as depicted above, showed significant HCVreplication inhibitory activity. These compounds were also effective ininhibiting HCV NS3 proteases of different HCV genotypes includinggenotypes 1, 2, 3 and 4. As a non-limiting example, representativecompounds in the preferred examples of formulae III, IV, VIII and IXshowed EC50s in the range of from less than 0.2 nM to about 10 nM usingcell-based replicon assays. Representative compounds of these preferredexamples also inhibited HCV NS3 proteases of different HCV genotypes,such as genotypes 1a, 1b, 2a, 2b, 3a, and 4a, with IC50s in the range offrom less than 0.2 nM to about 50 nM.

1. A compound represented by the formula I:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein: R₁ and R₂ are independently selected from the groupconsisting of: a) hydrogen; b) aryl; c) substituted aryl; d) heteroaryl;e) substituted heteroaryl; f) heterocyclic or substituted heterocyclic;g) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1,2, or 3 heteroatoms selected from O, S or N; h) substituted —C₁-C₈alkyl, substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; j) —C₃-C₁₂ cycloalkenyl,or substituted —C₃-C₁₂ cycloalkenyl; k) —B—R₃, where B is (CO), (CO)O,(CO)NR₄, (SO), (SO₂), (SO₂)NR₄; and R₃ and R4 are independently selectedfrom the group consisting of: (i) Hydrogen; (ii) aryl; (iii) substitutedaryl; (iv) heteroaryl; (v) substituted heteroaryl; (vi) heterocyclic;(vii) substituted heterocyclic; (viii) —C₁-C₈ alkyl; —C₂-C₈ alkenyl,—C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms selected fromO, S or N; (ix) substituted —C₁-C₈ alkyl; substituted —C₂-C₈ alkenyl;substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; (x) —C₃-C₁₂ cycloalkyl; substituted —C₃-C₁₂cycloalkyl; (xi) —C₃-C₁₂ cycloalkenyl, and substituted —C₃-C₁₂cycloalkenyl; alternatively, R₁ and R₂ taken together with the carbonatom to which they are attached form cyclic moiety consisting of:substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic;substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocycliceach fused with one or more R₃; where R₃ is as previously defined; G is-E-R₃ where E is absent, or E is O, CO, (CO)O, (CO)NH, NH, NH(CO),NH(CO)NH, NH(SO₂)NH or NHSO₂; where R₃ is as previously defined; Z isselected from the group consisting of CH₂, O, S, SO, or SO₂; A isselected from the group consisting of R₅, (CO)R₅, (CO)OR₅, (CO)NHR₅,SO₂R₅, (SO₂)OR₅ and SO₂NHR₅; R₅ is selected from the group consistingof: 1) aryl; 2) substituted aryl; 3) heteroaryl; 4) substitutedheteroaryl; 5) heterocyclic; 6) substituted heterocyclic; 7) —C₁-C₈alkyl; —C₂-C₈ alkenyl; -C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S or N; 8) substituted —C₁-C₈ alkyl;substituted —C₂-C₈ alkenyl; substituted —C₂-C₈ alkynyl each containing0, 1, 2, or 3 heteroatoms selected from O, S or N; 9) —C₃-C₁₂cycloalkyl; 10) substituted —C₃-C₁₂ cycloalkyl; 11) —C₃-C₁₂cycloalkenyl,; and 12) substituted —C₃-C₁₂ cycloalkenyl; j=0, 1, 2, or3; k=0, 1, 2, or 3;and m=0, 1, 2, or 3; n=1, 2 or 3; and h=0, 1, 2, or3.
 2. A compound according to claim 1 represented by formula II:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein A, G and R₁ are as previously defined in claim
 1. 3. Acompound according to claim 1 represented by formula III:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, where A, G, R₁ and R₂ are as previously defined in claim
 1. 4.A compound of formula IV:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein V is absent, or V is CO, O, S, SO, SO₂, NH or NCH₃, or(CH₂)_(q); where q is 1, 2, 3 or 4; and where X and Y are independentlyselected from the group consisting of: aryl; substituted aryl;heteroaryl; substituted heteroaryl; heterocyclic; and substitutedheterocyclic.
 5. A compound of claim 4, wherein

is selected from

where X₁-X₈ are independently selected from CH and N and X₁-X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or
 3. A can be selected from the group consisting of —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂-R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.
 6. A compound of claim 4, wherein

is selected from

where X₁-X₈ are independently selected from CH and N and X₁-X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or
 3. A can be selected from the group consisting of —C(O)—R₅,—C(O)—O—R₅ and —C(O)—NH—R₅, where R₅ is selected from aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —C₁-C₈ alkyl, —C₂-C₈ alkenyl, —C₂-C₈ alkynyl, substituted—C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, substituted —C₂-C₈ alkynyl,—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. G can be —O—R₃,—NH—C(O)—R₃, —NH—SO₂—NH—R₃ or —NHSO₂-R₃, where R₃ is selected fromhydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl.
 7. A compound of claim 4, wherein wherein

wherein X₁-X₈ are independently selected from CH and N and X₁-X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or
 3. A is —C(O)—O—R₅, where R₅ is —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃is selected from —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.8. A compound of claim 4, wherein wherein

is

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —C(O)—O—R₅, where R₅ is —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl. G is —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl.
 9. A compound of formula V:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, where X₁—X₄ are independently selected from CO, CH, NH, O andN; where X₁—X₄ can be further substituted when any one of X₁—X₄ is CH orNH; where R₆ and R₇ are independently R₃; where A, G and V are aspreviously defined in claim
 1. 10. A compound of formula VI:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, where Y₁—Y₃ are independently selected from CO, CH, NH, N, Sand O; and where Y₁—Y₃ can be further substituted when any one of Y₁—Y₃is CH or NH; Y₄ is selected from C, CH and N; where A, G, R₆, R₇ and Vare as previously defined in claim
 1. 11. A compound of claim 1repesented by formula VII:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein A, G and R₁ are as previously defined in claim
 1. 12. Acompound of claim 1, represented by formula VIII:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, where A, G, R₁ and R₂ are as previously defined in claim
 1. 13.A compound of formula IX:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein V is absent, or V is CO, O, S, SO, SO₂, NH or NCH₃, or(CH₂)_(q); where q is 1, 2, 3 or 4; and where X and Y are independentlyselected from the group consisting of: (i) aryl; substituted aryl; (ii)heteroaryl; substituted heteroaryl; (iii) heterocyclic; substitutedheterocyclic; where A and G are as previously defined in claim
 1. 14. Acompound of claim 13, wherein

is selected from

wherein X₁-X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH, and Y₁—Y₃ are independentlyselected from CH, N, NH, S and O and Y₁—Y₃ can be further substitutedwhen it is CH or NH; V is absent, CO, O, S, NH, or (CH₂)_(q), where q is1, 2 or
 3. A is —C(O)—O—R₅, where R₅ is —C₃-C₁₂ cycloalkyl, —C₃-C₁₂cycloalkenyl, substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkenyl. G is —NHSO₂—R₃, where R₃ is selected from aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl,substituted —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkenyl. 15.A compound of claim 13, wherein herein

wherein X₁—X₈ are independently selected from CH and N and X₁—X₈ can befurther substituted when it is a CH; V is absent, CO, O, S, NH, or(CH₂)_(q), where q is 1, 2 or
 3. A is —C(O)—O—R₅, where R₅ is —C₃-C₁₂cycloalkyl or substituted —C₃-C₁₂ cycloalkyl. G is —NHSO₂—R₃, where R₃is selected from —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂ cycloalkyl.16. A compound of claim 13, wherein herein

wherein Ra and Rb is independently selected from hydrogen or halogen. Ais —C(O)—O—R₅, where R₅ is —C₃-C₁₂ cycloalkyl or substituted —C₃-C₁₂cycloalkyl. G is —NHSO₂—R₃, where R₃ is selected from —C₃-C₁₂ cycloalkylor substituted —C₃-C₁₂ cycloalkyl.
 17. A compound of formula X:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, where X₁—X₄ are independently selected from CO, CH, NH, O andN; and wherein X₁—X₄ can be further substituted when any one of X₁—X₄ isCH or NH; where R₆ and R₇ are independently R₃; and where A, G and V areas previously defined in claim
 1. 18. A compound of formula XI:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, where Y₁—Y₃ are independently selected from CO, CH, NH, N, Sand O; and where Y₁—Y₃ can be further substituted when any one of Y₁—Y₃is CH or NH; Y₄ is selected from C, CH and N; and where A, G, R₆, R₇ andV are as previously defined.
 19. A compound of formula XII:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein: M₁ is selected from the group consisting of: (1)—N═CR₃₁R₃₂; wherein R₃₁ and R₃₂ are independently selected from thegroup consisting of: a) hydrogen; b) aryl; substituted aryl; c)heteroaryl; substituted heteroaryl; d) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or—C₂-C₈ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sor N; optionally substituted with one or more substituents selected fromhalogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;e) —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; heterocyclic orsubstituted heterocyclic; f) -A-R₃₀, where A is (CO), (CO)O, (CO)NR₄₀,(SO), (SO₂), (SO₂)NR₄₀; and R₃₀ and R₄₀ are independently selected fromthe group consisting of: (i) Hydrogen; (ii) aryl; substituted aryl;heteroaryl; substituted heteroaryl (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl,or —C₂-C₈ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O,S or N, optionally substituted with one or more substituents selectedfrom halogen, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; heterocyclicor substituted heterocyclic; with added proviso that when A=CO, (CO)O,(SO), (SO₂), R₃₀ is not hydrogen; with added proviso that whenR₃₁=hydrogen, R₃₂ is not hydrogen; alternatively, R₃₁ and R₃₂ are takentogether with the carbon atom to which they are attached to form thegroup consisting of: a) —C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂cycloalkyl; —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenylheterocyclic or substituted heterocyclic; b) —C₃-C₁₂ cycloalkyl,substituted —C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, or substituted—C₃-C₁₂ cycloalkenyl; heterocyclic or substituted heterocyclic fusedwith one or more substituents selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, —C₃-C₁₂ cycloalkyl, substituted—C₃-C₁₂ cycloalkyl, —C₃-C₁₂ cycloalkenyl, or substituted —C₃-C₁₂cycloalkenyl; heterocyclic or substituted heterocyclic; c)

wherein V is absent, or V is O, S, SO, SO₂, NR₅₀, or (CH₂)_(q); whereR₅₀ is selected from H, OH, OCH₃, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl, —O—C₃-C₈cycloalkyl, —C₃-C₈ cycloalkyl, —O—C₃-C₈ cycloalkenyl; —C₃-C₈cycloalkenyl; where q is 1, 2, 3 or 4; and where X and Y areindependently selected from the group consisting of: (i) aryl;substituted aryl; (ii) heteroaryl; substituted heteroaryl; (iii)heterocyclic; substituted heterocyclic; (2) NR₃₀R₄₀; NR₅(CO)R₃₀;NR₅₀(CO)OR₃₀; NR₅₀(CO)NR₃₀R₄₀; NR₅₀(SO₂)OR₃₀; NR₅₀(SO₂)NR₃₀R₄₀; whereR₃₀, R₄₀ and R₅₀ are as previously defined; alternatively, for formula(I), R₃₀ and R₄₀ are taken together with the nitrogen atom to which theyare attached to form the group consisting of: heterocyclic, orsubstituted heterocyclic; heteroaryl, or substituted heteroaryl; M₂ isselected from the group consisting of: (1) oxygen; (2) sulfur; (3) NR₆₀;where R₆₀ is selected from H, OH, OCH₃, —O—C₁-C₈ alkyl, —C₁-C₈ alkyl; Gis -E-R₃₀; and where E is absent, or E is O, CO, (CO)O, (CO)NH, NH,NH(CO), NH(CO)NH, NH(CNR₅₀)NH, NH(SO₂)NH or NHSO₂; where R₃₀ and R₅₀ areas previously defined; Z is selected from the group consisting of CH₂,O, CO, (CO)O, (CO)NH, S, SO, SO₂, CF, CF₂, aryl, substituted aryl,heteroaryl and substituted heteroaryl; n=0, 1, 2, 3 or 4; U is CH, CF orN; R₇₀ is selected from the group consisting of H, OH, OCH₃, —O—C₁-C₈alkyl, —C₁-C₈ alkyl; J is selected from the group consisting of CO,(CO)O, (CO)NR₅₀, SO₂, (SO₂)O or SO₂NR₅₀; R₈₀ is selected from the groupconsisting of: (1) hydrogen; (2) aryl; substituted aryl; heteroaryl;substituted heteroaryl; (3) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N,optionally substituted with one or more substituents selected fromhalogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;—C₃-C₁₂ cycloalkyl, or substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; heterocyclic orsubstituted heterocyclic; with added proviso that when J=CO, (CO)O,(SO), (SO₂), R₈₀ is not hydrogen; m=0, 1, 2 or 3; and s=0, 1, 2 or 3.20. A compound of formula XX:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein: R₁₀₁ and R₁₀₂ are independently selected from thegroup consisting of: a) hydrogen; b) aryl; c) substituted aryl; d)heteroaryl fused with 0, 1, 2, or 3 more group selected from heteroaryland aryl; e) substituted heteroaryl fused with 0, 1, 2 or 3 more groupselected from heteroaryl, substituted heteroaryl, aryl and substitutedaryl; f) heterocyclic, substituted heterocyclic, or oxo substitutedheterocyclic; wherein oxo refer to substituted by independentreplacement of two of the hydrogen atoms thereon with ═O; g) —C₁-C₈alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S or N; h) substituted —C₁-C₈ alkyl,substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; i) —C₃-C₁₂cycloalkyl, or —C₃-C₁₂ cycloalkenyl; j) substituted —C₃-C₁₂ cycloalkyl,or substituted —C₃-C₁₂ cycloalkenyl; k) oxo substituted —C₃-C₁₂cycloalkyl, or oxo substituted —C₃-C₁₂ cycloalkenyl; l) —B—R₁₀₃, where Bis (CO), (CO)O, (CO)NR₁₀₄, (SO), (SO₂), (SO₂)NR₁₀₄; and R₁₀₃ and R₁₀₄are independently selected from the group consisting of: (i) hydrogen;(ii) aryl; (iii) substituted aryl; (iv) heteroaryl fused with 0, 1,2, or3 more group selected from aryl and heteroaryl; (v) substitutedheteroaryl fused with 0, 1,2 or 3 more group selected from heteroaryl,substituted heteroaryl, aryl and substituted aryl; (vi) heterocyclic;(vii) substituted heterocyclic; (viii) oxo substituted heterocyclic;(ix) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each containing 0,1, 2, or 3 heteroatoms selected from O, S or N; (x) substituted —C₁-C₈alkyl, substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl eachcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N; (xi)—C₃-C₁₂ cycloalkyl, or —C₃-C₁₂ cycloalkenyl; (xii) substituted —C₃-C₁₂cycloalkyl, substituted —C₃-C₁₂ cycloalkenyl, oxo substituted —C₃-C₁₂cycloalkyl, or oxo substituted —C₃-C₁₂ cycloalkenyl; or R₁₀₁ and R₁₀₂taken together with the carbon atom to which they are attached form acyclic moiety selected from: substituted or unsubstituted cycloalkyl,cycloalkenyl, or heterocyclic; substituted or unsubstituted cycloalkyl,cycloalkenyl, or heterocyclic each substituted with an oxo; substitutedor unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic each fusedwith one or more R₁₀₃; or oxo substituted or unsubstituted cycloalkyl,cycloalkenyl, or heterocyclic each fused with one or more R₁₀₃; G₁ is-E-R₁₀₃, where E is absent or E is O, CO, (CO)O, (CO)NH, NH, NH(CO),NH(CO)NH, NH(SO₂)NH or NHSO₂; Z is selected from the group consisting ofCH₂, O, S, SO, or SO₂; A is selected from the group consisting of R₁₀₅,(CO)R₁₀₅, (CO)OR₁₀₅, (CO)NHR₁₀₅, SO₂R105₅, (SO₂)OR₁₀₅ and SO₂NHR₁₀₅;R₁₀₅ is selected from the group consisting of: aryl; a) hydrogen b)substituted aryl; c) heteroaryl fused with 0, 1, 2, or 3 more groupselected from heteroaryl and aryl; d) substituted heteroaryl fused with0, 1, 2 or 3 more group selected from heteroaryl, substitutedheteroaryl, aryl and substituted aryl; e) heterocyclic; f) substitutedheterocyclic; g) oxo substituted heterocyclic; h) —C₁-C₈ alkyl, —C₂-C₈alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatomsselected from O, S or N; i) substituted —C₁-C₈ alkyl, substituted —C₂-C₈alkenyl, or substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3heteroatoms selected from O, S or N; j) —C₃-C₁₂ cycloalkyl, or —C₃-C₁₂cycloalkenyl; k) substituted —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂cycloalkenyl, oxo substituted —C₃-C₁₂ cycloalkyl, or oxo substituted—C₃-C₁₂ cycloalkenyl; j=0, 1, 2, or 3; k=0, 1, 2, or 3;and m=0, 1, 2 or3; n=1, 2 or 3 and h=0, 1, 2, or
 3. 21. A compound of claim 1 having theFormula A selected from compounds 1-2 of Table 1: TABLE 1 (A)

Compound Rx G (1)

OEt (2)

OEt


22. A compound of claim 1 having the Formula B selected from compounds3-115 of Table 2: TABLE 2 (B)

Compound Rx R₁ R₂ G (3)

—CH₃ —Ph —OH (4)

—CH₂CH₃ —Ph —OH (5)

—CH₂CH₂CH₃ —Ph —OH (6)

—CH₂OCH₃ —Ph —OH (7)

—Ph —Ph —OH (8)

—Ph

—OH (9)

—Ph —OH (10)

—Ph —OH (11)

—Ph —OH (12)

—Ph —OH (13)

—H —Ph —OH (14)

—H

—OH (15)

—H

—OH (16)

—H

—OH (17)

—H

—OH (18)

—H

—OH (19)

—CH₂CH₃

—OH (20)

—H

—OH (21)

—H

—OH (22)

—H

—OH (23)

—H

—OH (24)

—H

—OH (25)

—H

—OH (26)

—H

—OH (27)

—H

—OH (28)

—H

—OH (29)

—H

—OH (30)

—H

—OH (31)

—H

—OH (32)

—H

—OH (33)

—H

—OH (34)

—H

—OH (35)

—H

—OH (36)

—H

—OH (37)

—H

—OH (38)

—H

(39)

—H

(40)

—H

(41)

—H

—OH (42)

—H

(43)

—Ph —Ph —OH (44)

—CH₃ —Ph —OH (45)

—H —Ph —OH (46)

—CH₃ —Ph

(47)

—CH₂CH₃ —Ph

(48)

—CH₂CH₂CH₃ —Ph

(49)

—CH₂OCH₃ —Ph

(50)

—Ph —Ph

(51)

—Ph

(52)

—Ph

(53)

—Ph

(54)

—Ph

(55)

—Ph

(56)

—H —Ph

(57)

—H

(58)

—H

(59)

—H

(60)

—H

(61)

—CH₂CH₃

(62)

—H

(63)

—H

(64)

—H

(65)

—H

(66)

—H

(67)

—H

(68)

—H

(69)

—H

(70)

—H

(71)

—H

(72)

—H

(73)

—H

(74)

—H

(75)

—H

(76)

—H

(77)

—H

(78)

—Ph —Ph

(79)

—CH₃ —Ph

(80)

—H —Ph

(81)

—CH₃ —Ph

(82)

—CH₂CH₃ —Ph

(83)

—CH₂CH₂CH₃ —Ph

(84)

—CH₂OCH₃ —Ph

(85)

—Ph —Ph

(86)

—Ph

(87)

—Ph

(88)

—Ph

(89)

—Ph

(90)

—Ph

(91)

—H —Ph

(92)

—H

(93)

—H

(94)

—H

(95)

—H

(96)

—H

(97)

—CH₂CH₃

(98)

—H

(99)

—H

(100)

—H

(101)

—H

(102)

—H

(103)

—H

(104)

—H

(105)

—H

(106)

—H

(107)

—H

(108)

—H

(109)

—H

(110)

—H

(111)

—H

(112)

—H

(113)

—H

(114)

—H

(115)

—H


23. A compound having the Formula B, Wherein R₁ and R₂ are takentogether with the carbon to which they are attached (R₁R₂), selectedfrom compounds 116-204 of Table 3: TABLE 3 Compound Rx R₁R₂ G (116)

—OH (117)

—OH (118)

—OH (119)

—OH (120)

—OH (121)

—OH (122)

—OH (123)

—OH (124)

—OH (125)

—OH (126)

—OH (127)

—OH (128)

—OH (129)

—OH (130)

—OH (131)

—OH (132)

—OH (133)

—OH (134)

(135)

—OH (136)

—OH (137)

(138)

(139)

—OH (140)

(141)

(142)

—OH (143)

(144)

(145)

—OH (146)

(147)

—OH (148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)


23. A compound according to claim 1 having the formula D:

W, Rx and G are delineated for each example in TABLE 4: TABLE 4 CompoundRx W G (205)

(206)

(207)

(208)


24. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt, ester, or prodrug thereof, in combination with apharmaceutically acceptable carrier or excipient.
 25. A method oftreating a hepatitis C viral infection in a subject, comprisingadministering to the subject the pharmaceutical composition according toclaim
 24. 26. A method of inhibiting the replication of hepatitis Cvirus, the method comprising contacting a hepatitis C virus with aneffective amount of a compound of claim
 1. 27. A method of claim 25further comprising administering an additional anti-hepatitis C virusagent.
 28. The method of claim 27, wherein said additionalanti-hepatitis C virus agent is selected from the group consisting ofα-interferon, β-interferon, ribavarin, and adamantine.
 29. The method ofclaim 28, wherein said additional anti-hepatitis C virus agent is aninhibitor of other targets in the hepatitis C virus life cycle which isselected from the group consisting of helicase, polymerase, metalloprotease, and IRES.
 30. A compound having a formula selected fromformulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV,XV, XVI, XVII, XVIII, XIX, or XX, as described in the specification, ora pharmaceutically acceptable salt, ester or prodrug thereof.
 31. Apharmaceutical composition comprising (1) a compound having a formulaselected from formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII,XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX as described in thespecification, or (2) a pharmaceutically acceptable salt, ester orprodrug of said compond.
 32. A process of making a compound having aformula selected from formulae I, II, III, IV, V, VI, VII, VIII, IX, X,XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, or XX as described in thespecification, according to the schemes and examples described therein.